Substituted oxindole derivatives, drugs containing said derivatives and the use thereof

ABSTRACT

The invention relates to novel oxindol derivative of general formula (I), wherein substituents R 1 , R 2 , A, B and Y are such as defined in a claim  1 . Drugs containing said derivatives and the use thereof for preventing and/or treating vassopress- and/or oxytocin-dependent-diseases are also disclosed.

The present invention relates to novel substituted oxindole derivatives,medicaments comprising them and the use thereof for the treatment ofdiseases.

Vasopressin is an endogenous hormone which exerts various effects onorgans and tissues. It is expected that the vasopressin system isinvolved in various pathological conditions such as, for example, heartfailure and high blood pressure. At present, three receptors (V1a, V1bor V3 and V2) via which vasopressin mediates its numerous effects areknown. Antagonists of these receptors are therefore investigated aspossible novel therapeutic approaches to the treatment of diseases (M.Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740). It has beenfound, for example, that a selective antagonist of the vasopressin V1breceptor exerts anxiolytic and antidepressant effects in animal models(Griebel et al., PNAS 2002, 99, 6370; Serradeil-Le Gal et al., J. Pharm.Exp. Ther. 2002, 300, 1122). Since the models described have a certainpredictive value for the clinical effects to be expected, antagonists ofthe V1b receptor are of particular interest for the treatment ofemotional disturbances or disorders such as, for example, stress,anxiety states and/or depression.

The present application describes novel substituted oxindoles which havea (hetero)arylsulfonyl group in position 1.1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones have previously beendescribed as ligands of the vasopressin receptors. WO 93/15051,WO95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO 01/64668 and WO01/98295 have described derivatives derived from the oxindole structureand having arylsulfonyl groups in position 1. These compounds differsubstantially in the substitution in position 3.

In particular, WO 93/15051 and WO 98/25901 describe1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones in which the oxindolestructure is substituted in position 3 by two alkyl radicals which maylikewise be a cycloalkyl radical (spirolinkage) as ligands ofvasopressin receptors. Alternative possibilities are for the spiro ringto comprise heteroatoms such as oxygen and nitrogen (optionally withsubstituents).

WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones whichhave a nitrogen atom in position 3 as ligands of vasopressin receptors.In addition, radicals which may be alkyl, cycloalkyl, phenyl or benzylradicals are linked in position 3 (in each case optionally withsubstituents).

Other publications, for example WO 01/55130, describe compounds whichhave nitrogen-containing rings (e.g. proline, homoproline, morpholine,tetrahydroisoquinoline, dihydroindole; in each case optionally withsubstituents) which are linked via their nitrogen atom to position 3 ofthe oxindole structure but which are substituted by phenylsulfonyl orphenyl groups (optionally with substituents) both in position 1 and inposition 3 on the oxindole ring.

WO 03/008407 describes 1-phenylsulfonyloxindoles in whichpyridylpiperazines are linked in position 3 via an oxycarbonyl group tothe oxindole.

It is an object of the present invention to provide further compoundsfor the treatment or prophylaxis of various vasopressin-dependentdiseases. The compounds are intended to show high activity, especiallyan antagonistic activity, on the human vasopressin V1b receptor.

The object is achieved by compounds of the general formula M.

-   -   in which    -   A is an aromatic, heteroaromatic, partly aromatic or partly        heteroaromatic mono- or bicyclic radical which consists of 2, 3,        4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen        atoms and/or 0, 1 or 2 oxygen atoms and/or 0, 1 or 2 sulfur        atoms, and which is substituted by the radical R_(A) ¹ and may        besides be additionally substituted by 1, 2 or 3 radicals R_(A)        ¹¹, R_(A) ¹² and/or R_(A) ¹³ which are selected independently of        one another and independent of their respective occurrence from        the group consisting of hydrogen, chlorine, bromine, iodine,        fluorine, CN, CF₃, OCF₃, OCHF₂, CO—NH₂, CO—NH(C₁-C₄-alkyl),        CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂, NH(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NHCHO, NH—CO—NH₂,        NH—CO(C₁-C₄-alkyl), NO₂, OH, O—C₁-C₄-alkyl,        O—C₀-C₄-alkylene-phenyl, phenyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,        C₂-C₆-alkenyl and C₂-C₆-alkynyl,    -   in which    -   R_(A) ¹ is R_(A) ²—(C₁-C₄-alkylene)-R_(A) ⁴,    -   R_(A) ² is selected from the group consisting of        -   (C₀-C₄-alkylene)-O, (C₀-C₄-alkylene)-NR_(A) ⁵,            (C₀-C₄-alkylene)-S, (C₀-C₄-alkylene)-SO,            (C₀-C₄-alkylene)-SO₂, (C₀-C₄-alkylene)-CO,            (C₀-C₄-alkylene)-NR_(A) ⁵—CO, (C₀-C₄-alkylene)-CO—NR_(A) ⁵,            (C₀-C₄-alkylene)-CO—O, (C₀-C₄-alkylene)-NR_(A) ⁵—SO₂,            (C₀-C₄-alkylene)-SO₂—NR_(A) ⁵, (C₀-C₄-alkylene)-NR_(A)            ⁵—CO—NR_(A) ⁶, (C₀-C₄-alkylene)-O—CO—NR_(A) ⁵,            (C₀-C₄-alkylene)-NR_(A) ⁵—CO—O and single bond,    -   R_(A) ⁴ is selected from the group consisting of        -   NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl),            NH(C₁-C₄-alkylene-O—N(C₁-C₄-alkyl)(C₁-C₄-alkylene-O—C₁-C₄-alkyl),            NH—CHO, N(C₁-C₄-alkyl)-CHO, NH—CO—NH₂,            N(C₁-C₄-alkyl)-CO—NH₂, NH—CO—C₁-C₄-alkyl,            N(C₁-C₄-alkyl)-CO—C₁-C₄-alkyl, NH—SO₂—C₁-C₄-alkyl,            N(C₁-C₄-alkyl)-SO₂—C₁-C₄-alkyl and ring R_(A) ⁸,    -   R_(A) ⁵, R_(A) ⁶, R_(A) ⁹ are selected independently of one        another and independent of their respective occurrence from the        group consisting of hydrogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl;    -   R_(A) ⁸ is selected from the group consisting of the respective        individual radicals

-   -   B is an aromatic, heteroaromatic, partly aromatic or partly        heteroaromatic mono- or bicyclic radical which consists of 2, 3,        4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen        atoms and/or 0, 1 or 2 oxygen atoms and/or 0, 1 or 2 sulfur        atoms, and which may be substituted by 1, 2 or 3 radicals R_(B)        ¹, R_(B) ² and/or R_(B) ³, where R_(B) ¹, R_(B) ² and R_(B) ³        are selected independently of one another and independent of        their respective occurrence from the group consisting of        hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃,        OCHF₂, CO—NH₂, CO—NH(C₁-C₄-alkyl),        CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂, NH(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH—CHO, NH—CO—NH₂,        NH—CO—C₁-C₄-alkyl, NO₂, OH, O—C₁-C₄-alkyl,        O—C₀-C₄-alkylene-phenyl, phenyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,        C₂-C₆-alkenyl and C₂-C₆-alkynyl;    -   R¹ is selected from the group consisting of hydrogen, chlorine,        bromine, iodine, fluorine, CN, CF₃, OCF₃, OCHF₂, CO—NH₂,        CO—NH(C₁-C₄-alkyl), CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂,        NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH—CHO, NH—CO—NH₂,        NH—CO—C₁-C₄-alkyl, NO₂, OH, O—C₁-C₄-alkyl,        O—C₀-C₄-alkylene-phenyl, phenyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl,        C₂-C₆-alkenyl and C₂-C₆-alkynyl,    -   R² is selected from the group consisting of hydrogen,        C₁-C₄-alkyl, O—C₁-C₄-alkyl, chlorine and fluorine,    -   Y is a radical

-   -   -   in which        -   R_(Y) ¹ is selected from the group consisting of hydrogen,            C₁-C₄-alkyl and C₁-C₄-haloalkyl;        -   R_(Y) ² is selected from the group consisting of hydrogen;            phenyl; phenyl substituted by 1, 2, 3, 4 or 5 radicals            R_(Ph) ¹, R_(Ph) ², R_(Ph) ³, R_(Ph) ⁴ and/or R_(Ph) ⁵ which            are selected independently of one another from the group            consisting of hydrogen, halogen, C₁-C₆-alkyl and            C₁-C₆-alkoxy; C₁-C₆-alkyl; C₃-C₇-cycloalkyl and            C₁-C₆-haloalkyl;

    -   in which R_(Y) ¹ and R_(Y) ² may also form together with the        atoms to which they are bonded a 4-, 5-, 6- or 7-membered,        saturated or unsaturated ring which may, instead of a ring C        atom, also include a heteroatom selected from the group        consisting of O, S and NR_(Y) ⁵ as further ring member, where        R_(Y) ⁵ may independent of its respective occurrence be        hydrogen, C₁-C₄-alkyl or CO—C₁-C₄-alkyl, and where the ring may        have one or two substituents R_(Y) ⁶ and R_(Y) ⁷ which are        selected independently of one another and independent of their        respective occurrence from the group consisting of the radicals        hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃,        OCHF₂, CO—NH₂, CO—NH(C₁-C₄-alkyl),        CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂, NH(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH—CHO, NH—CO—NH₂,        NH—CO—C₁-C₄-alkyl, OH, O—C₁-C₄-alkyl, O—CO—C₁-C₄-alkyl,        O—(CH₂)₀₋₂-phenyl, phenyl, C₁-C₆-alkyl,

    -   or

    -   R_(Y) ⁶ and R_(Y) ⁷ may also independent of their respective        occurrence form together with the C atoms to which they are        bonded a fused phenyl ring or a fused 5- or 6-membered, aromatic        heterocycle which, besides C atoms, includes as ring members 1,        2, 3 or 4 identical or different heteroatoms as ring members        which may be selected independently of one another from the        group consisting of nitrogen, oxygen and sulfur,

    -   R_(Y) ³ is selected from the group consisting of hydrogen,        C₁-C₄-alkyl and C₁-C₄-haloalkyl;

    -   R_(Y) ⁴ is selected from the group consisting of hydrogen,        CO—NR_(Y) ²¹R_(Y) ²², CO—C₁-C₄-alkyl, COOH and CO—O—C₁-C₄-alkyl,

    -   R_(Y) ²¹, R_(Y) ²² are selected independently of one another and        independent of their respective occurrence from the group        consisting of hydrogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl;

    -   or R_(Y) ²¹ and R_(Y) ²² may also independent of their        respective occurrence form together with the nitrogen atom to        which they are bonded a 4-, 5- or 6-membered, saturated or        wholly or partly unsaturated N-heterocyclic ring,

    -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

    -   R_(A) ⁴ is in particular selected from the group consisting of        NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)(C₁-C₄-alkylene-O—C₁-C₄-alkyl), NH—CHO, NH—CO—NH₂,        NH—CO—C₁-C₄-alkyl and ring R_(A) ⁸.

A preferred embodiment relates to compounds of the general formula (I)in which the variables have independently of one another the followingmeanings:

-   -   A is an aromatic or heteroaromatic monocyclic radical having 2,        3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, which        may besides comprise additionally 0, 1, 2 or 3 identical or        different heteroatoms independently of one another selected from        the group consisting of nitrogen, oxygen and sulfur, as ring        members, and is substituted by the radical R_(A) ¹ and may        besides be substituted by one, two or three radicals R_(A) ¹¹,        R_(A) ¹² and/or R_(A) ¹³ which are selected independently of one        another and independent of their respective occurrence from the        group consisting of hydrogen, chlorine, fluorine, O—C₁-C₄-alkyl,        C₁-C₄-alkyl and C₁-C₄-haloalkyl,    -   in which    -   R_(A) ¹ is R_(A) ²—(C₁-C₄-alkylene)-R_(A) ⁴;    -   R_(A) ² is selected from the group consisting of        (C₀-C₄-alkylene)-O, (C₀-C₄-alkylene)-NR_(A) ⁵,        (C₀-C₄-alkylene)-S, (C₀-C₄-alkylene)-SO, (C₀-C₄-alkylene)-SO₂,        (C₀-C₄-alkylene)-CO, (C₀-C₄-alkylene)-NR_(A) ⁵—CO,        (C₀-C₄-alkylene)-CO—NR_(A) ⁵, (C₀-C₄-alkylene)-CO—O and single        bond;    -   R_(A) ⁴ is selected from the group consisting of NH₂,        NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)(C₁-C₄-alkylene-O—C₁-C₄-alkyl) and ring R_(A) ⁸;    -   R_(A) ⁵, R_(A) ⁹ are selected independently of one another and        independent of their respective occurrence from the group        consisting of hydrogen and C₁-C₄-alkyl;    -   R_(A) ⁸ is selected independent of its respective occurrence        from the group consisting of the respective individual radicals

-   -   B is an aromatic or heteroaromatic mono- or bicyclic radical        having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members,        which may additionally comprise 1, 2 or 3 identical or different        heteroatoms selected independently of one another from the group        consisting of nitrogen, oxygen and sulfur as ring members, and        which may be substituted by one, two or three radicals R_(B) ¹,        R_(B) ² and/or R_(B) ³, where R_(B) ¹, R_(B) ² and R_(B) ³ are        selected independently of one another and independent of their        respective occurrence from the group consisting of hydrogen,        chlorine, bromine, fluorine, CN, CF₃, OCF₃, OCHF₂,        O—C₁-C₄-alkyl, C₁-C₄-alkyl and C₁-C₄-haloalkyl;    -   R¹ is selected from the group consisting of hydrogen, bromine,        chlorine, fluorine, CN, CF₃, OCF₃, O—C₁-C₄-alkyl, C₁-C₄-alkyl,        C₁-C₄-haloalkyl and C₂-C₄-alkynyl,    -   R² is selected from the group consisting of hydrogen,        C₁-C₄-alkyl, C₁-C₄-halo-alkyl, O—C₁-C₄-alkyl, chlorine and        fluorine,    -   Y is a radical

-   -   -   in which        -   R_(Y) ¹ is selected from the group consisting of hydrogen            and C₁-C₄-alkyl;        -   R_(Y) ² is selected from the group consisting of hydrogen,            phenyl, C₁-C₆-alkyl, and C₃-C₇-cycloalkyl,        -   in which R_(Y) ¹ and R_(Y) ² may also form together with the            atoms to which they are bonded a 4-, 5-, 6- or 7-membered,            saturated or unsaturated ring which may, instead of a C atom            as ring member, also include a hetero-atom selected from the            group consisting of O and NR_(Y) ⁵, as further ring member,            where R_(Y) ⁵ may independent of its respective occurrence            be hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl or CO—C₁-C₄-alkyl,            and where the ring may have one or two substituents R_(Y) ⁶            and/or R_(Y) ⁷ which are selected independently of one            another and independent of their respective occurrence from            the group consisting of the radicals hydrogen, fluorine, CN,            OH, O—C₁-C₄-alkyl, O—CO—C₁-C₄-alkyl, O—(CH₂)₀₋₂-Phenyl,            phenyl and C₁-C₄-alkyl;        -   or        -   R_(Y) ⁶ and R_(Y) ⁷ may independent of their respective            occurrence also form together with the C atoms to which they            are bonded a fused phenyl ring (benzo ring);

    -   R_(Y) ³ is selected from the group consisting of hydrogen and        methyl,

    -   R_(Y) ⁴ is selected from the group consisting of CO—NR_(Y)        ²¹R_(Y) ²², CO—C₁-C₄-alkyl and CO—O—C₁-C₄-alkyl,

    -   R_(Y) ²¹, R_(Y) ²² are selected independently of one another and        independent of their respective occurrence from the group        consisting of hydrogen and C₁-C₄-alkyl;

    -   or

    -   R_(Y) ²¹ and R_(Y) ²² may independent of their respective        occurrence also form together with the nitrogen atom to which        they are bonded a 4-, 5- or 6-membered, saturated or unsaturated        N-heterocyclic ring,

    -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

A further preferred embodiment relates to compounds of the generalformula (I) in which the variables have independently of one another thefollowing meanings:

-   -   A is a cyclic radical which is selected from the group        consisting of phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl        and pyridazinyl, and which is substituted by the radical R_(A) ¹        and may besides be additionally substituted by one or two        radicals R_(A) ¹¹ and/or R_(A) ¹² which are selected        independently of one another and independent of their respective        occurrence from the group consisting of hydrogen, chlorine,        methoxy, ethoxy, propoxy, methyl, ethyl and propyl;    -   in which    -   R_(A) ¹ is R_(A) ²—(C₁-C₄-alkylene)-R_(A) ⁴,    -   in which    -   R_(A) ² is selected from the group consisting of O, CH₂—O,        NR_(A) ⁵, CH₂—NR_(A) ⁵, NR_(A) ⁵—CO, CH₂—NR_(A) ⁵—CO and a        single bond;    -   R_(A) ⁴ is selected from the group consisting of NH₂,        NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl),        N(C₁-C₄-alkyl)(C₁-C₄-alkylene-O—C₁-C₄-alkyl) and ring R_(A) ⁸;    -   R_(A) ⁵, R_(A) ⁹ are selected independently of one another and        independent of their respective occurrence from the group        consisting of hydrogen and C₁-C₄-alkyl;    -   R_(A) ⁸ is selected from the group consisting of the respective        individual radicals

-   -   B is an aromatic or heteroaromatic mono- or bicyclic radical        having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members,        which may comprise 1, 2 or 3 identical or different heteroatoms        selected independently of one another from the group consisting        of nitrogen, oxygen and sulfur as ring member, and which may be        substituted by one or two radicals R_(B) ¹ and/or R_(B) ², where        R_(B) ¹ and R_(B) ² are selected independently of one another        from the group consisting of hydrogen, chlorine, fluorine, CN,        O—C₁-C₄-alkyl and C₁-C₄-alkyl;    -   R¹ is selected from the group consisting of hydrogen, chlorine,        fluorine, CN, methoxy and methyl;    -   R² is selected from the group consisting of hydrogen, chlorine        and methyl;    -   Y is a radical

-   -   -   in which        -   R_(Y) ¹ is selected from the group consisting of hydrogen            and C₁-C₄-alkyl;        -   R_(Y) ² is selected from the group consisting of hydrogen,            phenyl and C₁-C₄-alkyl;        -   where R_(Y) ¹ and R_(Y) ² may also form together with the            atoms to which they are bonded a 5- or 6-membered, saturated            or unsaturated ring which, instead of a C atom as ring            member, may also include a heteroatom selected from the            group consisting of O and NR_(Y) ⁵ as further ring member,            where R_(Y) ⁵ may independent of its respective occurrence            be hydrogen, C₁-C₄-alkyl, or CO—C₁-C₄-alkyl, and where the            ring may have one or two substituents R_(Y) ⁶ and/or R_(Y) ⁷            which are selected independently of one another and            independent of their respective occurrence from the group            consisting of the radicals hydrogen, fluorine, OH and            O—C₁-C₄-alkyl,        -   or        -   R_(Y) ⁶ and R_(Y) ⁷ may independent of their respective            occurrence also form together with the C atoms to which they            are bonded a fused phenyl ring (benzo ring);

    -   R_(Y) ³ is selected from the group consisting of hydrogen and        methyl;

    -   R_(Y) ⁴ is CO—NR_(Y) ²¹R₂₂,

    -   in which

    -   R_(Y) ²¹, R_(Y) ²² are selected independently of one another        from the group consisting of hydrogen and C₁-C₄-alkyl;

    -   or

    -   R_(Y) ²¹ and R_(Y) ²² may independent of their respective        occurrence also form together with the nitrogen atom to which        they are bonded a 4-, 5- or 6-membered, saturated or unsaturated        N-heterocyclic ring;

    -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

A further preferred embodiment relates to compounds of the generalformula (I) in which the variables have independently of one another thefollowing meanings:

-   -   A is a radical selected from the group consisting of the        respective individual radicals

-   -   in which    -   R_(A) ¹¹ is selected independent of its respective occurrence        from the group consisting of hydrogen, chlorine, methoxy and        ethoxy;    -   R_(A) ¹ is a radical selected from the group consisting of the        respective individual radicals

-   -   B is a cyclic radical selected from the group consisting of        phenyl, pyridyl, thienyl and quinolinyl, which may in each case        be substituted by 1 or 2 radicals R_(B) ¹ and/or R_(B) ², where        R_(B) ¹ and R_(B) ² are selected independently of one another        from the group consisting of hydrogen, chlorine, fluorine, CN,        methyl and methoxy;    -   R¹ is selected from the group consisting of hydrogen, chlorine,        fluorine, CN, methoxy and methyl;    -   R² is selected from the group consisting of hydrogen and        chlorine;    -   Y is a radical selected from the group consisting of the        respective individual radicals

Me=CH₃

-   -   R_(Y) ⁴ is CO—NR_(Y) ²¹R_(Y) ²², where R_(Y) ²¹ and R_(Y) ²² are        selected independently of one another from the group consisting        of hydrogen, methyl and ethyl;    -   or    -   R_(Y) ²¹ and R_(Y) ²² may independent of their respective        occurrence also form together with the nitrogen atom to which        they are bonded a 4-, 5- or 6-membered, saturated or unsaturated        or partly unsaturated N-heterocyclic ring;    -   R_(Y) ⁵ is selected from the group consisting of the radicals        hydrogen, C₁-C₄-alkyl, and CO—C₁-C₄-alkyl;    -   R_(Y) ⁶ is selected from the group consisting of the radicals        hydrogen, fluorine, OH and O—C₁-C₄-alkyl,    -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

A further preferred embodiment relates to compounds of the generalformula (I) in which the variables have independently of one another thefollowing meanings:

-   -   A is phenyl which, besides the radical R_(A) ¹, may carry a        further radical R_(A) ¹¹ which is selected from Cl and        C₁-C₄alkoxy and which is preferably linked in the position ortho        to the point of linkage of the phenyl ring to the remainder of        the molecule, e.g. a radical selected from the group consisting        of the respective individual radicals

-   -   R_(A) ¹ is a radical selected independent of its respective        occurrence from the group consisting of the respective        individual radicals

-   -   B is a cyclic radical selected from the group of phenyl,        pyridyl, thienyl and quinolinyl, each of which may carry one or        two radicals R_(B) ¹, R_(B) ² where B is in particular one of        the radicals:

-   -   -   in which        -   R_(B) ¹ and R_(B) ² are selected independently of one            another and independent of their respective occurrence from            the group consisting of hydrogen, chlorine, fluorine, CN,            methyl and methoxy;

    -   R¹ is selected from the group consisting of chlorine, methoxy        and CN;

    -   R² is hydrogen;

    -   Y is selected from the group consisting of the respective        individual radicals

Me=CH₃

-   -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

A further preferred embodiment relates to compounds of the generalformula (I) in which the variables have independently of one another thefollowing meanings:

-   -   A is selected from the group consisting of the respective        individual radicals

-   -   -   in which        -   R_(A) ¹ is a radical selected independent of its respective            occurrence from the group consisting of the respective            individual radicals

-   -   B is a cyclic radical selected from the group consisting of the        respective individual radicals

-   -   R¹ is chlorine;    -   R² is hydrogen;    -   Y is a radical selected from the group consisting of the        respective individual radicals

-   -   Me=CH₃    -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

A further preferred embodiment relates to compounds of the generalformula (I) in which the variables have independently of one another thefollowing meanings:

-   -   A is a radical selected from the group consisting of the        respective individual radicals

-   -   R_(A) ¹ is a radical selected independent of its respective        occurrence from the group consisting of the respective        individual radicals

-   -   B is a cyclic radical selected from the group consisting of the        respective individual radicals

-   -   R¹ is chlorine;    -   R² is hydrogen;    -   Y is a radical selected from the group consisting of the        respective individual radicals

-   -   Me=CH₃    -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

A further preferred embodiment relates to compounds of the generalformula (I) in which the variables have independently of one another thefollowing meanings:

-   -   A is a cyclic radical selected from the group consisting of the        respective individual radicals

-   -   in which    -   R_(A) ¹ is a radical selected from the group consisting of the        respective individual radicals

-   -   B is a cyclic radical selected from the group consisting of the        respective individual radicals

-   -   R¹ is chlorine,    -   R² is hydrogen,    -   Y is selected from the group consisting of the respective        individual radicals

-   -   the tautomeric, enantiomeric and diastereomeric forms thereof,        and the prodrugs thereof, and the physiologically tolerated        salts of said compounds.

A further preferred embodiment relates to compounds of the generalformula (I) in which the radical R¹ is linked at position 5 of theoxindole ring structure.

A further preferred embodiment relates to compounds of the generalformula (I) where the compound of the general formula (I) is an enrichedoptically active isomer having an optical purity greater than 50% basedon the optically inactive mixture of the isomeric mixture which rotatesthe plane of polarized light to the left (“negative rotation”).

A further preferred embodiment relates to compounds of the generalformula (I) where the optically active isomer is an enantiomericallyenriched diastereomer.

A further preferred embodiment relates to compound of the generalformula (I) in which the property of “negative rotation” relates to thefree base.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than about 100 nM, preferably not more than 10nM, in particular not more than 1 nM and specifically not more than 0.1nM, e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 toless than 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to10 nM or 1 to 10 nM.

A further preferred embodiment relates to compounds of the generalformula (I) which have a selectivity for the vasopressin V1b receptorsubtype vis-à-vis the vasopressin V1a receptor subtype, where thequotient of Ki(V1a)/Ki(V1b) is greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a selectivity for the vasopressin V1b receptorsubtype vis-à-vis the vasopressin V2 receptor subtype, where thequotient of Ki(V2)/Ki(V1b) is greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a selectivity for the vasopressin V1b receptorsubtype vis-à-vis the oxytocin (OT) receptor, where the quotient ofKi(OT)/Ki(V1b) is greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than 100 nM, preferably not more than 10 nM, inparticular not more than 1 nM and specifically not more than 0.1 nM,e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to lessthan 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nMor 1 to 10 nM, and a selectivity for the vasopressin V1b receptorsubtype vis-à-vis the vasopressin V1a receptor subtype, where thequotient of Ki(V1a)/Ki(V1b) is greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than 100 nM, preferably not more than 10 nM, inparticular not more than 1 nM and specifically not more than 0.1 nM,e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to lessthan 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nMor 1 to 10 nM, and a selectivity for the vasopressin V1b receptorsubtype vis-à-vis the vasopressin V2 receptor subtype, where thequotient of Ki(V2)/Ki(V1b) is greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than 100 nM, preferably not more than 10 nM, inparticular not more than 1 nM and specifically not more than 0.1 nM,e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to lessthan 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nMor 1 to 10 nM, and a selectivity for the vasopressin V1b receptorsubtype vis-à-vis the oxytocin (OT) receptor, where the quotient ofKi(OT)/Ki(V1b) is greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than 100 nM, preferably not more than 10 nM, inparticular not more than 1 nM and specifically not more than 0.1 nM,e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to lessthan 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nMor 1 to 10 nM, and selectivities for the vasopressin V1b receptorsubtype vis-à-vis the vasopressin V1a receptor subtype and thevasopressin V2 receptor subtype, where the quotients of Ki(V1a)/Ki(V1b)and Ki(V2)/Ki(V1b) are in each case greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than 100 nM, preferably not more than 10 nM, inparticular not more than 1 nM and specifically not more than 0.1 nM,e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to lessthan 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nMor 1 to 10 nM, and simultaneous selectivities for the vasopressin V1breceptor subtype vis-à-vis the vasopressin V1a receptor subtype and theoxytocin (OT) receptor, where the quotients of Ki(V1a)/Ki(V1b) andKi(OT)/Ki(V1b) are in each case greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than 100 nM, preferably not more than 10 nM, inparticular not more than 1 nM and specifically not more than 0.1 nM,e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to lessthan 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nMor 1 to 10 nM, and simultaneous selectivities for the vasopressin V1breceptor subtype vis-à-vis the vasopressin V2 receptor subtype and theoxytocin (OT) receptor, where the quotients of Ki(V2)/Ki(V1b) andKi(OT)/Ki(V1b) are in each case greater than 1.

A further preferred embodiment relates to compounds of the generalformula (I) which have a binding affinity Ki for the vasopressin V1breceptor subtype of less than 100 nM, preferably not more than 10 nM, inparticular not more than 1 nM and specifically not more than 0.1 nM,e.g. 0.01 to less than 100 nM, or 0.1 to less than 100 nM or 1 to lessthan 100 nM or 10 to less than 100 nM or 0.01 to 10 nM, or 0.1 to 10 nMor 1 to 10 nM, and simultaneous selectivities for the vasopressin V1breceptor subtype vis-à-vis the vasopressin V1a receptor subtype, thevasopressin V2 receptor subtype and the oxytocin (OT) receptor, wherethe quotients of Ki(V1a)/Ki(V1b), Ki(V2)/Ki(V1b) and Ki(OT)/Ki(V1b) arein each case greater than 1.

A further aspect of the present invention relates to compounds of thegeneral formula (I) for use as medicament.

A further aspect of the present invention relates to a medicamentcomprising at least one compound of the general formula (I).

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of at least one vasopressin-dependent and/oroxytocin-dependent disease and/or for the manufacture of a medicamentfor the treatment and/or prophylaxis of at least one of said diseases.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of at least one disorder selected from the group consistingof diabetes insipidus, nocturnal enuresis, incontinence, diseases inwhich blood coagulation disorders occur, and/or for delaying micturitionand/or for the manufacture of a medicament for the treatment and/orprophylaxis of at least one of said diseases.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of at least one disorder selected from the group consistingof hypertension, pulmonary hypertension, heart failure, myocardialinfarction, coronary spasm, unstable angina, PTCA (percutaneoustransluminal coronary angioplastie), ischemias of the heart, disordersof the renal system, edemas, renal vasospasm, necrosis of the renalcortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disordersof the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis,gastric and intestinal ulcer, emesis, emesis occurring duringchemotherapy, and/or travel sickness and/or for the manufacture of amedicament for the treatment and/or prophylaxis of at least one of saiddiseases.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of affective disorders and/or for the manufacture of amedicament for the treatment of affective disorders.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of anxiety disorders and/or stress-dependent anxietydisorders and/or for the manufacture of a medicament for the treatmentof anxiety disorders and/or stress-dependent anxiety disorders.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of memory impairments and/or Alzheimer's disease and/or forthe manufacture of a medicament for the treatment and/or prophylaxis ofmemory impairments and/or Alzheimer's disease.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of psychoses and/or psychotic disorders and/or for themanufacture of a medicament for the treatment and/or prophylaxis ofpsychoses and/or psychotic disorders.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of Cushing's syndrome and/or for the manufacture of amedicament for the treatment and/or prophylaxis of Cushing's syndrome.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of sleep disorders and/or for the manufacture of amedicament for the treatment and/or prophylaxis of sleep disorders.

A further aspect of the present invention relates to the use of at leastone compound of the general formula (I) for the treatment and/orprophylaxis of depressive disorders and/or for the manufacture of amedicament for the treatment and/or prophylaxis of depressive disorders.

A further aspect of the present invention relates to a method for thetreatment and/or prophylaxis of at least one disorder selected from thegroup consisting of diabetes insipidus, nocturnal enuresis,incontinence, diseases in which blood coagulation disorders occur, andfor delaying micturition in a patient, where an effective amount of atleast one compound of the general formula (I) is administered to thepatient.

A further aspect of the present invention relates to a method for thetreatment and/or prophylaxis of at least one disorder selected from thegroup consisting of hypertension, pulmonary hypertension, heart failure,myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplastie), ischemias of theheart, disorders of the renal system, edemas, renal vasospasm, necrosisof the renal cortex, hyponatremia, hypokalemia, Schwartz-Barttersyndrome, disorders of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurringduring chemotherapy, and travel sickness in a patient, where aneffective amount of at least one compound of the general formula (I) isadministered to the patient.

A further aspect of the present invention relates to a method for thetreatment and/or prophylaxis of affective disorders in a patient, wherean effective amount of at least one compound of the general formula (I)is administered to the patient.

A further aspect of the present invention relates to a method for thetreatment of anxiety disorders and/or stress-dependent anxiety disordersin a patient, where an effective amount of at least one compound of thegeneral formula (I) is administered to the patient.

A further aspect of the present invention relates to a method for thetreatment of memory impairments and/or Alzheimer's disease in a patient,where an effective amount of at least one compound of the generalformula (I) is administered to the patient.

A further aspect of the present invention relates to a method for thetreatment of psychoses and/or psychotic disorders in a patient, where aneffective amount of at least one compound of the general formula (I) isadministered to the patient.

A further aspect of the present invention relates to a method for thetreatment of Cushing's syndrome in a patient, characterized in that aneffective amount of at least one compound of the general formula (I) isadministered to the patient.

A further aspect of the present invention relates to a method for thetreatment of sleep disorders in a patient, where an effective amount ofat least one compound of the general formula (I) is administered to thepatient.

A further aspect of the present invention relates to a method for thetreatment of depressive disorders in a patient, where an effectiveamount of at least one compound of the general formula (I) isadministered to the patient.

A further aspect of the present invention relates to a method for thetreatment and/or prophylaxis of vasomotor disorders in a patient, wherean effective amount of at least one compound of the general formula (I)is administered to the patient.

A further aspect of the present invention relates to a method for thetreatment and/or prophylaxis of disorders associated with drugwithdrawal in a patient, where an effective amount of at least onecompound of the general formula (I) is administered to the patient.

In a preferred embodiment, the methods described above are characterizedby the patient being a mammal, preferably a human or a non-human or anon-human transgenic mammal.

A further aspect of the present invention relates to a method forpreparing compounds of the general formula (I), where the compounds ofthe general formula (I) can be prepared by carrying out and/or carryingout analogously method steps known per se to the relevant skilledworker.

Each of these preferred definitions of a variable can be combined withany of the definitions of the remaining variables.

A further embodiment provides at least one compound of the inventionwith the general formula (I) selected from the group consisting of theexamples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101 and 102, and thetautomeric, enantiomeric and diastereomeric forms thereof, and theprodrugs thereof, and non-salt forms and other physiologically toleratedsalts of the aforementioned compounds.

The compounds of the invention may be in the form of a mixture ofdiastereomers, a mixture of diastereomers in which one of the twodisastereomers is enriched, or of diastereomerically pure compounds(de>90%). The compounds are preferably in the form of diastereomericallypure compounds. The respective diastereomers may in turn be in the formof a mixture of enantiomers (for example as racemate), of a mixture ofenantiomers in which one of the two enantiomers is enriched, or ofenantiomerically pure compounds (ee>90%). The respective diastereomersare preferably in the form of enantiomerically pure compounds. Compoundswhich are diastereomerically pure and enantiomerically pure (de>90%,ee>90%) are particularly preferred.

Physiologically tolerated salts in the sense of the description may,unless stated otherwise, be formed for example with the followinganions:

chloride, bromide, phosphate, carbonate, nitrate, perchlorate, sulfate,citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate,ascorbate, cinnamate, glycolate, methanesulfonate, formate, malonate,naphthalene-2-sulfonate, tosylates, salicylate, trifluoroacetate and/oracetate. Further suitable acid are listed for example in “Fortschritteder Arzneimittelforschung”, 1966, Birkhäuser Verlag, Vol. 10, pp.224-285.

In the sense of the present description, unless stated otherwise, theterms “alkyl”, “cycloalkyl”, “alkoxy”, “haloalkyl” “alkenyl”, “alkynyl”or “alkylene”, and radicals derived therefrom, always comprise bothunbranched and branched “alkyl”, “cycloalkyl”, “alkoxy”, “haloalkyl”,“alkenyl”, “alkynyl” or “alkylene”.

C₀-alkylene or (CH₂)₀ or similar expressions designate in the sense ofthe description, unless stated otherwise, a single bond or hydrogen.

The terms C₁-C₆-alkyl and C₁-C₄-alkyl mean in the sense of thedescription, unless stated otherwise, a straight-chain or branchedsaturated hydrocarbon chain with the number indicated in each case ofcarbon atoms respectively from 1 to 6 and from 1 to 4 carbon atoms suchas, for example, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutylor 1-ethyl-2-methylpropyl, preferably methyl, ethyl, propyl, n-butyl ori-butyl. C₁-C₄-alkyl is in the sense of the description, unless statedotherwise, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl,sec-butyl or t-butyl.

The term “C₁-C₆-alkoxy” means in the sense of the description, unlessstated otherwise, a C₁-C₆-alkyl group which is as defined above and islinked via oxygen.

The terms C₁-C₆-alkylene and C₀-C₄-alkylene (with C₀-alkylene=singlebond) mean in the sense of the description, unless stated otherwise, analkyl group which has respectively 1 to 6 and 0 to 4 C atoms, which isdefined as previously and in which one hydrogen atom is replaced by abond. Examples which should be particularly mentioned are methylene,eth-1,2-ylene, prop-1,2-ylene, prop-1,3-ylene, but-1,2-ylene,but-1,3-ylene, but-2,3-ylene, but-1,4-ylene, 2-methylprop-1,3-ylene,pent-1,2-ylene, pent-1,3-ylene, pent-1,4-ylene, pent-1,5-ylene,pent-2,3-ylene, pent-2,4-ylene, 1-methylbut-1,4-ylene,2-methylbut-1,4-ylene, 2-methylbut-1,3-ylene, 2-ethylprop-1,3-ylene,hex-3,4-ylene, 3-methylpent-2,4-ylene, hept-3,5-ylene,2-ethylpent-1,3-ylene, 3-ethylhept-3,5-ylene, etc., preferablymethylene, eth-1,2-ylene and prop-1,2-ylene.

The term C₃-C₇-cycloalkyl means in the sense of the description, unlessstated otherwise, a saturated hydrocarbon ring having 3 to 7 carbon ringmembers, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

C₁-C₆-haloalkyl or C₁-C₄-haloalkyl is in the sense of the description,unless stated otherwise, a C₁-C₆-alkyl or C₁-C₄-alkyl as defined abovein which one, more than one or all hydrogen atoms have been replaced byidentical or different halogen atoms as defined below.

The term C₂-C₆-alkenyl means in the sense of the description, unlessstated otherwise, a branched or unbranched hydrocarbon chain comprisingat least one double bond and having 2 to 6 carbon atoms. C₂-C₆-alkenylpreferably comprises one or two double bonds, most preferably one doublebond. Examples of the alkenyl groups are those mentioned above foralkyl, with these groups comprising one or two double bonds, such as,for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl,2-methyl-4-pentenyl, 3-methyl-4-entenyl, 4-methyl-4-pentenyl,1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl,1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, inparticular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or3-methyl-2-pentenyl.

The term C₂-C₆-alkynyl means in the sense of the description, unlessstated otherwise, a branched or unbranched hydrocarbon chain comprisingat least one triple bond and having 2 to 6 carbon atoms. C₂-C₆-alkynylpreferably comprises one or two triple bonds, most preferably one triplebond. Examples of alkynyl groups are those mentioned above for alkyl,with these groups comprising one or two triple bonds, such as, forexample, ethynyl, 1-propynyl, 1-butynyl, 1-methyl-2-propynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl,1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl,1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl,1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl,2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably ethynyl,1-propynyl, 1-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.

The terms “3- to 10-membered carbocycle” or “4 to 7 membered carbocyclicring” or “carbocyclic ring having 3 to 10 C atoms” mean in the sense ofthe description, unless stated otherwise, a saturated or wholly orpartly unsaturated hydrocarbon ring having 3 to 10 carbon atoms or 4 to7 C atoms as ring atoms, such as, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl orcyclodecanyl. Where explicitly mentioned, the carbocyclic ring may alsocomprise heteroatoms as ring atoms and is then referred to asheterocycle or heterocyclic ring. The heterocyclic ring has 2 to 10carbon atoms and the number indicated in each case of heteroatoms asring members. The heterocyclic ring may be saturated or partlyunsaturated or aromatic (also referred to as heteroaromatichereinafter). Monocyclic heteroaromatic rings typically have 5 or 6 ringatoms.

Halogen is in the sense of the description, unless stated otherwise, ahalogen atom selected from fluorine, chlorine, bromine or iodine,preferably fluorine, chlorine or bromine, more preferably fluorine orchlorine.

The expressions “C₁-C₆-haloalkyl” or “C₁-C₄-haloalkyl” designate in thesense of the description, unless stated otherwise, an alkyl radical asdefined above which is partially or completely substituted by one ormore identical or different radicals selected independently of oneanother from the group consisting of fluorine, chlorine, bromine andiodine, thus for example CH₂F, CHF₂, CF₃, CH₂Cl, 2-fluoroethyl,2-chloroethyl, 2,2,2-trifluoroethyl.

Where appropriately described by use of the expression “substituted”,the radicals and groups can in the sense of the description, unlessstated otherwise, be substituted, preferably one or more times, morepreferably once, twice or three times, most preferably once or twice.The expression “in each case optionally substituted” is intended to makeit clear that not only the radical immediately following but also allthe radicals mentioned in the respective group may be substituted.

Examples of suitable substituents in the sense of the descriptioninclude, unless stated otherwise: halogen, CN, CF₃, CHF₂, OCF₃, OCHF₂,NO₂, NH₂, OH, COOH, in each case branched or unbranched, optionallysubstituted C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₆-alkylene-O—C₁-C₆-alkylor C₁-C₆-thioalkyl, O—C₁-C₄-alkyl, N(C₁-C₄-alkyl)₂, NH(C₁-C₄-alkyl),aryl, —O-aryl, C₁-C₄-alkylene-O-aryl, NHCO—C₁-C₄-alkyl,NH—SO₂—C₁-C₄-alkyl, CO—C₁₋₄-alkyl, SO₂—C₁-C₄-alkyl, and, optionallysubstituted in the aryl radical, NHCO-aryl, NHSO₂-aryl, CONH₂, SO₂NH₂,SO₂-aryl, SO—C₁-C₄-alkyl, SO-aryl, N-pyrrolidinyl, N-piperidinyl, andN-morpholinyl. Preferred substituents are F, Cl, CF₃, OCF₃, NH₂, NO₂,OH, COOH, C₁-C₄-alkyl, methoxy, acetyl, NH-acetyl and SO₂NH₂.

Expressions in parentheses with subscript integers are to be understoodin the sense of the description, unless stated otherwise, in such a waythat the meanings of the radicals in parentheses may in each case beidentical or different. For example, N(C₁-C₄-alkyl)₂ stands in the senseof the description for N(C₁-C₄-alkyl)(C₁-C₄-alkyl), where the two(C₁-C₄-alkyl) radicals may be identical or different.

The symbol (*) in the chemical formulae of R¹, R², A, B and Y in thegeneral formula (I) describes in the sense of the description, unlessstated otherwise, the points of linkage of said radicals to the oxindolering structure or a group connected to the oxindole ring structure.

The symbol (______) describes in the sense of the description, unlessstated otherwise, a single bond which—if linked to a center ofchirality—is intended to mean that the corresponding compound are in theform either of an approximately 1:1 mixture (racemate, (R/S) form) ofthe two enantiomeric forms in relation to the center of chirality, orelse of separate enantiomers (R) and/or (S) in relation to the center ofchirality.

The symbol —SO— means in the sense of the description, unless statedotherwise, a sulfoxide group (—S(═O)—).

The symbol —SO₂— means in the sense of the description, unless statedotherwise, alternatively a radical selected from the group consisting ofthe sulfone (—(O═S═O)—) and the sulfinic acid group (—(S═O)—O—), withthe meaning of the sulfone group being preferably meant.

Where two radicals form a ring together with the atoms to which they arebonded, for example the radicals R_(Y) ¹ and R_(Y) ² or the radicalsR_(Y) ²¹ and R_(Y) ²², the ring atoms defined by the radicals are carbonatoms unless indicated otherwise. Thus, for example, the radicals R_(Y)¹ and R_(Y) ² may form together with the nitrogen atom and the carbonatom to which they are bonded a 4-, 5-, 6- or 7-membered nitrogenheterocycle which, besides the nitrogen atom to which R_(Y) ¹ is bonded,includes 3, 4, 5 or 6 carbon atoms as ring members or 2, 3, 4 or 5carbon atoms and a further heteroatom which is selected from O, S andNR_(Y) ⁵ as ring members. Thus, for example, the radicals R_(Y) ²¹ andR_(Y) ²² may form together with the nitrogen atom to which they arebonded a 4-, 5- or 6-membered nitrogen heterocycle which is saturated orwholly or partly unsaturated and, besides the nitrogen atom, comprises3, 4 or 5 carbon atoms as ring members.

The expression “aromatic, heteroaromatic, partly aromatic or partlyheteroaromatic mono- or bicyclic ring” means in the sense of thedescription, unless stated otherwise, a mono- or bicyclic ring which iscomposed of C atoms (“aromatic” or “partly aromatic”) or of acombination of C atoms and heteroatoms (“heteroaromatic” or “partlyheteroaromatic”) in each case as ring members, and includes an aromaticnumber of double bonds in the ring (“monocyclic”) or in the two rings(“bicyclic”) (“aromatic” or “heteroaromatic”) or only in one of therings (“partly aromatic” or “partly heteroaromatic”). Aromatic andheteroaromatic rings comprise in particular 5- or 6-membered monocycles,and bicyclic systems of two fused 5- or 6-membered monocycles.

Examples of aromatic rings are phenyl, naphthyl, fluorenyl, indenyl andphenanthrenyl, more preferably phenyl and naphthyl, such as 1-naphthylor 2-naphthyl. Phenyl is most preferred.

Examples of heteroaromatic rings are 2-furyl, 3-furyl, 2-pyrrolyl,3-pyrrolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, thiadiazolyl, oxadiazolyl, triazinyl, indolinyl,benzothienyl, naphthothienyl, benzofuranyl, chromenyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl,quinoxalinyl, benzimidazolyl and benzoxazolyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl-,2,1,3-benzothiadiazolyl.

The expressions “saturated or wholly or partly unsaturated carbocyclicring” or “saturated or unsaturated carbocyclic ring” mean in the senseof the description, unless stated otherwise, a ring or ring system whichis in each case formed of C atoms and has no double bond located in thering (“saturated”) or has one or more double bonds which are conjugatedor unconjugated or only in part conjugated with one another (“partly orwholly unsaturated” or “unsaturated”). The carbocyclic ring may be amono-, bi- or tricyclic ring. A bi- or tricyclic, saturated carbocyclemay in the sense of the description, unless stated otherwise, be abicycloalkyl or tricycloalkyl radical having 5 to 10 carbon atoms. Inthe case of a bicycloalkyl radical, the ring system may preferablycomprise 5 to 10, more preferably 6 to 10, carbon atoms. In the case ofa tricycloalkyl radical, the ring system preferably comprises 6 to 10,more preferably 7 to 10, carbon atoms. Examples of a bicycloalkylradical include camphyl and norbornyl. Examples of a tricycloalkylradical include adamantyl.

The expressions “saturated or wholly or partly unsaturated heterocyclicring” or “saturated or unsaturated heterocyclic ring” mean in the senseof the description, unless stated otherwise, a ring or ring system whichis formed in each case of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms andthe indicated number of heteroatoms and which has no double bond locatedin the ring (“saturated”) or has one or more double bonds which areconjugated or unconjugated or conjugated only in part with one another(“partly or wholly unsaturated” or “unsaturated”). The heterocyclic ringmay be a mono-, bi- or tricyclic ring. A bi- or tricyclic, saturatedheterocycle may in the sense of the description, unless statedotherwise, be a bicycle or tricycle having 5 to 10 ring atoms. In thecase of a bicyclic ring, the ring system may preferably comprise 5 to10, more preferably 6 to 10, ring atoms. In the case of a tricycle, thering system preferably comprises 6 to 10, more preferably 7 to 10, ringatoms. An example of a bicycle which comprises carbon atoms and anitrogen atom as ring members is indolyl.

The expression “in the sense of the description” includes the presentapplication in all its parts, that is in particular the description, theclaims, the drawings and the abstract.

The compounds of the invention are effective after administration byvarious routes (for example intravenously, intramuscularly, orally),especially orally.

The compounds of the invention show good affinity for vasopressinreceptors, especially the vasopressin V1b receptor subtype. Since thevarious vasopressin receptors mediate very different effects ofvasopressin (M. Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5),729-740; Serradeil-Le Gal, C, et al.; Prog Brain Res. 2002;139:197-210), it is particularly important to obtain effects selectivelyon, for example, one vasopressin receptor, in order thus to achieve thedesired effect without simultaneously causing considerable side effects.Thus, vasopressin mediates for example effects on the kidney and itsfunction via the V2 receptor, and this would be unwanted during apossible treatment of CNS disorders. Accordingly, besides the actualaffinity for the target receptor, also particularly important is theselectivity vis-à-vis the other vasopressin receptors. A high affinityfor a vasopressin receptor may likewise be advantageous because thedesired effect is then achieved even with low serum levels, so that sideeffects can be reduced or even avoided in this way. The compounds of theinvention show the advantage of having very good affinities for inparticular the vasopressin V1b receptor and simultaneously generallydisplaying an improved selectivity vis-à-vis the other receptors such asV2.

The present invention also provides the use of the compounds of theinvention for the treatment and/or prophylaxis of diseases in which thecourse of the disease is at least partially dependent on vasopressin,i.e. diseases which show an elevated vasopressin or oxytocin level whichmay contribute directly or indirectly to the pathological state.

The present invention further provides the use of the compounds of theinvention for the treatment and/or prophylaxis of diseases such as, forexample, diabetes insipidus, nocturnal enuresis, incontinence, diseasesin which blood coagulation disorders occur and/or for delayingmicturition.

The present invention also provides the use of the compounds of theinvention for the treatment and/or prophylaxis of the followingdiseases: hypertension, pulmonary hypertension, heart failure,myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplastie), ischemias of theheart, disorders of the renal system, edemas, renal vasospasm, necrosisof the renal cortex, hyponatremia, hypokalemia, Schwartz-Barttersyndrome, disorders of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurringduring chemotherapy, and travel sickness.

The compounds of the invention can also be used for the treatment ofvarious vasopressin-dependent or oxytocin-dependent complaints whichhave central nervous causes or alterations in the HPA axis (hypothalamicpituitary adrenal axis), for example for affective disorders such asdepressive disorders and bipolar disorders. These include for exampledythymic disorders, phobias, post-traumatic stress disorders, generalanxiety disorders, panic disorders, seasonal depressions and sleepdisorders. The disorders which can be treated according to the inventionand which are associated with alterations in the HPA axis also includethe disorders associated with drug withdrawal, especially withdrawal ofopioid drugs or cocaine, including the increased tendency to relapse offormerly dependent individuals.

The compounds of the invention can likewise be employed for treatment incases of anxiety disorders and stress-dependent anxiety disorders suchas, for example, generalized anxiety disorders, phobias, post-traumaticanxiety disorders, panic anxiety disorders, obsessive-compulsive anxietydisorders, acute stress-dependent anxiety disorders and social phobia.The inventive compounds can further be employed also for the treatmentof memory impairments, Alzheimer's disease, psychoses, psychoticdisorders, sleep disorders and/or Cushing's syndrome.

The compounds of the invention are further suitable for the treatment ofpsychotic disorders/impairments such as schizophrenia.

The compounds of the invention are further suitable for the treatment ofvasomotor disorders (vasomotor symptoms VMS) such as hot flushes ornight sweats, and thus also for the prophylaxis of the sequelaeassociated therewith, such as lack of sleep and disorders andimpairments resulting therefrom.

The present invention also relates to pharmaceutical compositions whichcomprise an effective dose of a compound of the invention or of apharmaceutically acceptable salt thereof and suitable pharmaceuticalcarriers.

These pharmaceutical carriers are chosen according to the pharmaceuticalform and the desired mode of administration.

The compounds of the invention of the general formula I or optionallysuitable salts of these compounds can be used to produce pharmaceuticalcompositions for oral, sublingual, subcutaneous, intramuscular,intravenous, topical, intratracheal, intranasal, transdermal or rectaladministration and can be administered to animals or humans in standardadministration forms, mixed with conventional pharmaceutical carriers,for the prophylaxis or treatment of the above disorders or diseases.

The suitable standard administration forms comprise forms for oraladministration, such as tablets, gelatin capsules, powders, granules andsolutions or suspensions for oral intake, forms for sublingual, buccal,intratracheal or intranasal administration, aerosols, implants, forms ofsubcutaneous, intramuscular or intravenous administration and forms ofrectal administration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active basic ingredient can vary between 0.01 and 50 mg perkg of body weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose may be administered 1 to 5 times a day, so thata daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the mainingredient is mixed with a pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative oranother suitable substance, or be treated otherwise in order to displaya sustained or delayed activity and in order to release a predeterminedamount of the active basic ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and including the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may comprise active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable color.

Water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agents,such as polyvinylpyrrolidones, and sweeteners or masking flavors.

Rectal administration is achieved by using suppositories which areprepared with binders which melt at the rectal temperature, for examplecocoa butter or polyethylene glycols. Parenteral administration iseffected by using aqueous suspensions, isotonic saline solutions orsterile and injectable solutions which comprise pharmacologicallyacceptable dispersants and/or wetting agents, for example propyleneglycol or polyethylene glycol.

The active basic ingredient may also be formulated as microcapsules orcentrosomes, where suitable with one or more carriers or additives.

In addition to the compounds of the general formula (I) or theirpharmaceutically acceptable salts, the compositions of the invention maycomprise other active basic ingredients which may be beneficial for thetreatment of the disorders or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active basic ingredients arepresent together, at least one of these being a compound of theinvention.

The compounds of the invention represent antagonists of the so-calledreceptors of the vasopressin/oxytocin family. Such compounds can beinvestigated in suitable assays which ascertain the affinity for areceptor, where the affinity constant Ki represents a measure of thepotency of the compounds and a smaller value represents a greaterpotency. The compounds of the invention have been tested for example fortheir receptor affinity in the following vasopressin receptor subtypeV1b receptor for their affinity.

Preparation of the Compounds of the Invention

Examples of synthetic routes for preparing the compounds of theinvention are described hereinafter.

The oxindoles of the invention can be prepared for example by the routeoutlined in synthesis scheme 1. The variables in synthesis schemes 1have the same meanings as in the general formula (I)

Compounds in which an amino group R_(A) ⁴ is linked via a methylenegroup to ring A can be synthesized in the manner shown in synthesisscheme 1. The 3-hydroxyoxindoles VI can be prepared by addition oforganolithium or Grignard compounds onto the 3-keto group of thesubstituted isatins V in an ethereal solvent such as, for example,tetrahydrofuran (THF). For example (R_(A) ¹¹═OCH₃) the lithium speciescan be obtained from the iodoaryl compound IV by treatment withorganolithium reagents such as, for example, n-butyllithium in THF atlow temperatures. Alternatively, the corresponding Grignard compound canbe prepared from IV by treatment with magnesium in an ethereal solventsuch as, for example, THF. The cyclic acetal IV can be prepared in twostages (methylation of the phenol oxygen followed by protection of thealdehyde as acetal) from commercially available3-hydroxy-4-iodobenzaldehyde (II). The isomeric building block(protected aldehyde function para to the methoxy group) can be obtainedin an analogous way from 3-bromo-4-methoxybenzaldehyde, which can bebought. Compounds with R_(A) ¹¹═H can be synthesized by reactingGrignard compounds which can be bought, e.g.(3-(1-Pyrrolidinylmethyl)phenyl)magnesium bromide or(4-(1-pyrrolidinylmethyl)phenyl)magnesium bromide, with the isatins V.

In the case where A is an aromatic heterocycle, metallatedheteroaromatic compounds having a protected formyl group can be preparedin an analogous manner (protection of the formyl function as cyclicacetal followed by lithium-halogen exchange or insertion of magnesiuminto the heteroaryl-halogen bond), e.g. from commercially available2-bromo-4-formyl-3-methoxypyridine, 6-bromo-2-formylpyridine,5-bromo-3-formylpyridine, 2-bromo-4-formylpyridine,2-bromo-5-formylpyridine, 4-bromo-2-formylthiophene,3-bromo-2-formylthiophene, 5-bromo-2-formylthiophene or3-bromo-4-formylthiophene.

The 3-hydroxyoxindoles VI can be converted into the compounds VII havinga leaving group LG in position 3, it being possible for the leavinggroup LG to be usual leaving groups such as, for example, halides,mesylate or tosylate. Thus, for example (LG=chlorine), the intermediateVII can be prepared by treating the alcohol VI with thionyl chloride inthe presence of a base such as, for example, pyridine, in a solvent suchas, for example, dichloromethane. The compounds VII are then reacted inthe presence of a base such as, for example, N,N-diisopropylethylaminewith primary or secondary amines Y—H such as, for example,(S)-pyrrolidine-2-dimethylcarboxamide (H-Pro-NMe₂),(2S,4R)-4-hydroxy-pyrrolidine-2-dimethylcarboxamide (H-Hyp-NMe₂) or(S)-N,N-di-methyl-2-methylaminopropionamide (H-MeAla-NMe₂), in a solventsuch as, for example, dichloromethane, to give the corresponding3-aminooxindoles VIII. After cleavage of the acetal protective group,e.g. by treatment with aqueous hydrochloric acid in acetone, theresulting aldehyde IX can be reacted with primary or secondary amines inthe presence of a reducing agent such as, for example, sodiumcyanoborohydride or solid phase-bound triacetoxyborohydride, in asolvent such as, for example, THF, to give the amines X (Reductiveamination: J. March, Advanced Organic Chemistry, 1992, 4th edition.,Wiley, New York, p. 411; 898). Sulfonylation of the oxindole nitrogencan take place by treatment of X with sulfonyl chlorides B—SO₂Cl afterdeprotonation with a strong base such as, for example, potassiumtert-butoxide or sodium hydride, in a solvent such as, for example,N,N-dimethylformamide (DMF) or THF.

The cyano group as radical R¹ can be introduced starting from thecorresponding compounds with R¹=iodine, for example by heating compoundX or XI (with R¹═I) with zinc cyanide in DMF in the presence ofcatalytic amounts of palladium tetrakis-(triphenylphosphine) or byheating with potassium cyanide and catalytic amounts of palladiumtetrakis(triphenylphosphine) in THF (J. Med. Chem. 1996, 39, 5072-5082).

Compounds in which an amino group R_(A) ⁴ is linked via an O-alkylenegroup to ring A can be synthesized in the manner shown in synthesisscheme 2. The 3-hydroxyoxindoles XII can be prepared by addition oforganolithium or Grignard compounds onto the 3-keto group of thesubstituted isatins V. For example (R_(A) ¹¹═OCH₃), the correspondinglithium species can be obtained from 4-bromo-3-methoxyphenol afterprotection of the phenolic oxygen function with a suitable protectivegroup PG, such as, for example, triisopropylsilyl, by treatment withorganolithium reagents such as, for example, n-butyllithium, in anethereal solvent such as, for example, THF, at low temperatures.Introduction of the leaving group LG, replacement of the leaving groupLG by amines Y—H and sulfonylation of the oxindole nitrogen took placeas described previously (synthesis scheme 1) and afforded the protectedcompound XV. After removal of the protective group PG, in the case ofPG=triisopropylsilyl for example with tetrabutylammonium fluoride inTHF, the phenolic oxygen function can be alkylated with alkyl halideswhich comprise substituted amino groups R_(A) ⁴, e.g. by heating thephenol XVI with the alkylating agent R_(A) ⁴—(C₂-C₄-alkyl)-Cl in DMF inthe presence of a base such as potassium carbonate in a microwave.

The invention is explained in more detail below by means of exampleswithout being restricted to the examples.

EXPERIMENTAL SECTION Example 1(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt A)2-(4-Iodo-3-methoxyphenyl)-5,5-dimethyl[1,3]dioxane

Sodium hydride (887 mg, 60% dispersion in mineral oil, 22.2 mmol) wasadded to an ice-cooled solution of 3-hydroxy-4-iodobenzaldehyde (5.00 g,20.2 mmol) in DMF (20 ml) and stirred at 0° C. for 60 min. Iodomethane(3.15 ml, 22.2 mmol) was added dropwise to the solution of thephenolate, and the reaction mixture was stirred at room temperature for4 h. The mixture was diluted with ethyl acetate and washed withice-water and saturated sodium chloride solution. After drying overmagnesium sulfate, the organic phase was concentrated under reducedpressure. The residue (6.32 g) was dissolved in toluene (150 ml) and,after addition of neopentyl glycol (2.76 g, 26.5 mmol) and Amberlyst-15(400 mg), the reaction mixture was heated under reflux with a water trapfor 3 h. After filtration, the reaction solution was concentrated underreduced pressure and the residue was purified by chromatography onsilica gel (mobile phase gradient 10-25% ethyl acetate indichloromethane). Yield: 6.83 g (77%) of a yellowish oil. MS (API-ES,pos) m/z=349 [M+H]⁺

B)5-Chloro-3-[4-(5,5-dimethyl[1,3]dioxan-2-yl)-2-methoxyphenyl]-3-hydroxy-1,3-dihydro-indol-2-one

A solution of n-butyllithium in hexane (1.6 m, 5.52 ml, 8.83 mmol) wasslowly added dropwise to a solution of2-(4-iodo-3-methoxyphenyl)-5,5-dimethyl[1,3]dioxane (3.00 g, 8.62 mmol)in THF (100 ml) at −78° C. After 15 min, a solution of 5-chloroisatinsodium salt [prepared by treating a solution of 5-chloroisatin (1.21 g,6.64 mmol) in THF with one equivalent of sodium hydride at 0° C. for oneh] was added dropwise to the solution of the organolithium species. Thereaction mixture is allowed to warm to room temperature and then stirredfor one further hour. Aqueous ammonium chloride solution was added tothe reaction solution with stirring, and the mixture was extracted withethyl acetate. The combined organic phase was washed with water andsaturated sodium chloride solution, dried over magnesium sulfate andconcentrated under reduced pressure. The desired product crystallizes onstanding in the cold. Yield: 1.42 g (53%) of a white solid. MS (API-ES,pos) m/z=404 [M+H]⁺

C)(S)-1-{5-Chloro-3-[4-(5,5-dimethyl[1,3]dioxan-2-yl)-2-methoxyphenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,mixture of diastereomers

Pyridine (0.68 ml, 8.43 mmol) and thionyl chloride (0.61 ml, 8.43 mmol)were added to a solution of the reaction product from stage 1B (2.84 g,7.02 mmol) in dichloromethane (20 ml) while cooling in ice, and themixture was stirred at 0° C. for 15 min. The reaction solution wasquenched with water while stirring, and the mixture was extracted withdichloromethane. The organic phase was washed with water and saturatedsodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. N,N-Diisopropylethylamine (3.32 ml, 19.1 mmol)and (S)-pyrrolidine-2-dimethylcarboxamide (1.00 g, 7.01 mmol) were addedto a solution of the 3-chlorooxindole intermediate obtained in this wayin dichloromethane (20 ml), and the reaction mixture was stirred at roomtemperature for 18 h. After dilution with dichloromethane, the mixturewas washed with water and saturated sodium chloride solution, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (mobile phase gradient 1-5%methanol in dichloromethane). Yield: 3.08 g (79%) of a mixture ofdiastereomers. MS (API-ES, pos) m/z=528 [M+H]⁺

D)(S)-1-[5-Chloro-3-(4-formyl-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-dimethylcarboxamide,mixture of diastereomers

A solution of the reaction product from stage 1C (1.00 g, 1.89 mmol) ina mixture of acetone (15 ml), dichloromethane (2 ml) and 2 N aqueoushydrochloric acid (10 ml) was stirred at room temperature for 72 h. Thereaction was completed by heating at 50° C. for 45 min. The reactionmixture was diluted with dichloromethane and neutralized by addingsodium bicarbonate solution. The organic phase was washed with saturatedsodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. Yield: 650 mg (78%) of a white solid. MS(API-ES, pos) m/z=442 [M+H]⁺

E)(S)-1-[5-Chloro-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-dimethylcarboxamide,levorotatory diastereomer

-   -   Pyrrolidine (0.15 ml, 1.77 mmol) and        MP-triacetoxyborohydride-resin (Argonaut, 2.04 g, f=1.8 mmol/g,        3.68 mmol) were added to a solution of the reaction product from        stage 1D (650 mg, 1.47 mmol) in THF (5 ml) and the mixture was        shaken at room temperature for 16 h. The solid-phase reagent was        filtered off and washed with THF, and the filtrate was        concentrated under reduced pressure. The residue was purified by        chromatography on silica gel (mobile phase gradient 5-25%        methanol in dichloromethane). Yield: 156 mg (21%) of the        levorotatory diastereomer which elutes earlier, MS (API-ES, pos)        m/z=497 [M+H]⁺, [α]_(D)-124 (c 0.1, CHCl₃, 20° C.); 87 mg of the        diastereomer which elutes later, MS (API-ES, pos) m/z=497        [M+H]⁺.

F)(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt (Example 1)

Sodium hydride (3 mg, 60% dispersion in mineral oil, 0.08 mmol) wasadded to a solution of the reaction product from stage 1E (30 mg of thelevorotatory diastereomer which elutes earlier, 0.06 mmol) in DMF (2 ml)at 0° C. After 30 min, 2,4-dimethoxybenzenesulfonyl chloride (15 mg,0.06 mmol) was added to the reaction solution and stirred at roomtemperature for a further 30 min. Sodium bicarbonate solution was addedto the mixture, which was then extracted with ethyl acetate. Thecombined organic phase was washed with water and saturated sodiumchloride solution, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by preparative HPLC (mobilephase gradient 10-100% acetonitrile in water+0.1% trifluoroacetic acid).Yield: 20 mg (48%), MS (API-ES, pos) m/z=697 [M+H]⁺.

Example 2(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideA)(S)-1-[5-Chloro-3-[4-(5,5-dimethyl[1,3]dioxan-2-yl)-2-methoxyphenyl]-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,mixture of diastereomers

Sodium hydride (136 mg, 60% dispersion in mineral oil, 3.41 mmol) wasadded to a solution of the reaction product from stage 1C (1500 mg, 2.84mmol) in DMF (10 ml) at 0° C. After 30 min, 4-methoxybenzenesulfonylchloride (616 mg, 2.98 mmol) was added to the reaction solution andstirred at room temperature for a further 30 min. Sodium bicarbonatesolution was added to the mixture, which was then extracted with ethylacetate. The combined organic phase was washed with water and saturatedsodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. Purification by chromatography on silica gel(mobile phase gradient 2-10% CH₃OH in dichloromethane) afforded 1.71 g(86%) of the desired product as mixture of diastereomers. MS (API-ES,pos) m/z=698 [M+H]⁺.

B)(S)-1-[5-Chloro-3-(4-formyl-2-methoxyphenyl)-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,levorotatory diastereomer

A solution of the reaction product from stage 2A (1.71 g, 2.45 mmol) ina mixture of acetone (25 ml) and 2 N aqueous hydrochloric acid (20 ml)was stirred at room temperature for 18 h. The reaction mixture wasdiluted with dichloromethane and neutralized by adding sodiumbicarbonate solution. The reaction mixture was extracted twice withdichloromethane. The organic phase was washed with water, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (mobile phase gradient10-20% ethyl acetate in dichloromethane). Yield: 634 mg (42%) of thelevorotatory diastereomer. MS (API-ES, pos) m/z=612 [M+H]⁺; [α]_(D)-180(c 0.1, CHCl₃, 20° C.)

C)(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

A solution of the reaction product from stage 2B (350 mg, 0.57 mmol) inTHF (4 ml) was mixed with pyrrolidine (0.06 ml, 0.7 mmol) andMP-triacetoxyborohydride-resin (Argonaut, 560 mg, f=2.6 mmol/g, 1.5mmol) and shaken at room temperature for 16 h. The solid-phase reagentwas filtered off and washed with THF, and the solution was concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel (mobile phase gradient 2-10% methanol in dichloromethane).Yield: 289 mg (76%). MS (API-ES, pos) m/z=667 [M+H]⁺; ¹H NMR (400 MHz,d₆-DMSO) 8.10 (d, 2H), 7.80 (m, 1H), 7.55 (d, 1H), 7.40 (d, 1H), 7.20(d, 2H), 6.90 (m, 2H), 6.80 (s, 1H), 4.45 (m, 1H), 3.85 (s, 3H), 3.50(m, 2H), 3.10 (br m, 2H), 2.55 (m, 2H), 2.40 (m, 7H), 1.80 (m, 1H), 1.70(m, 4H), 1.45 (m, 2H).

In many cases, the products of the reductive amination were purified bypreparative reversed phase HPLC (mobile phase: gradient from 10% to 80%acetonitrile in water, 0.1% trifluoroacetic acid) and accordingly resultas trifluoroacetic acid salts.

The following compounds 3 to 16 were prepared in an analogous manner tothat described for Examples 1 and 2 (synthesis scheme 1).(2S,4R)-4-Hydroxy-pyrrolidine-2-dimethylcarboxamide (H-Hyp-NMe₂) and(S)-N,N-dimethyl-2-methylaminopropionamide (H-MeAla-NMe₂) were preparedas described in WO05030755.

Example 3(S)-1-[5-Chloro-1-(4-fluorobenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=655 [M+H]⁺.

Example 4(S)-1-[5-Chloro-1-(4-chlorobenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=671 [M+H]⁺.

Example 5(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=662 [M+H]⁺.

Example 6(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-2-oxo-3-(4-pyrrolidin-1-yl-methylphenyl)-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=683 [M+H]⁺.

Example 7(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(4-dimethylaminomethyl-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidin-2-dimethylcarboxamide

MS (API-ES, pos) m/z=671 [M+H]⁺.

Example 8(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-4-piperidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=711 [M+H]⁺.

Example 9(S)-1-{5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-[2-methoxy-4-(4-methyl-piperazin-1-ylmethyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=726 [M+H]⁺.

Example 10(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-4-morpholin-4-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=713 [M+H]⁺.

Example 11(S)-1-[3-[4-(4-Acetylpiperazin-1-ylmethyl)-2-methoxyphenyl]-5-chloro-1-(2,4-dimethoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=754 [M+H]⁺.

Example 12(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(4-{[(2-dimethylaminoethyl)-methylamino]methyl}-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=728 [M+H]⁺.

Example 13

(S)-2-{[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(4-dimethylaminomethyl-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]methylamino}-N,N-dimethyl-propionamide

MS (API-ES, pos) m/z=659 [M+H]⁺.

Example 14(S)-2-{[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]methylamino}-N,N-dimethyl-propionamide

MS (API-ES, pos) m/z=685 [M+H]⁺.

Example 15(S)-2-({5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-[2-methoxy-4-(4-methyl-piperazin-1-ylmethyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}methylamino)-N,N-dimethyl-propionamide

MS (API-ES, pos) m/z=714 [M+H]⁺.

Example 16(2S,4R)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(3-dimethylaminomethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=657 [M+H]⁺.

Example 17

(S)-1-[5-Chloro-3-(5-dimethylaminomethyl-2-methoxyphenyl)-1-(4-methoxy-benzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

A) 2-(3-Bromo-4-methoxyphenyl)-5,5-dimethyl[1,3]dioxane

3-Bromo-4-methoxybenzaldehyde (60.0 g, 279 mmol) was dissolved intoluene (600 ml) and, after addition of neopentyl glycol (32.0 g, 306mmol) and Amberlyst 15 (3.6 g), the reaction mixture was heated underreflux with a water trap for 2 h. After cooling, the reaction mixturewas filtered, washed twice with water and then concentrated underreduced pressure. The remaining oil was mixed with heptane, whereuponthe product precipitates and was filtered off and washed with heptane.Yield: 57.3 g (68% of theory).

MS (API-ES, pos) m/z=301, 303 [M+H]⁺

B)5-Chloro-3-[5-(5,5-dimethyl-[1,3]dioxan-2-yl)-2-methoxyphenyl]-3-hydroxy-1,3-dihydroindol-2-one

Magnesium turnings (2.2 g, 89 mmol) were introduced into THF (30 ml) andetched with some iodine crystals. While stirring, a solution of2-(3-bromo-4-methoxy-phenyl)-5,5-dimethyl-[1,3]dioxane (26.0 g, 86 mmol)in THF (80 ml) was added thereto. After the reaction started(identifiable by the evolution of heat), the rate of dropwise additionwas slowed down so that the reaction mixture just continued to boil. Thereaction mixture was then stirred for 20 min and subsequently cooled toroom temperature. The Grignard solution obtained in this way was pumpedinto an ice-cooled solution of 5-chloroisatin sodium salt [prepared bytreating a solution of 5-chloroisatin (13.1 g, 72 mmol) in THF (400 ml)with one equivalent of sodium hydride at 0° C. for one h] and thenstirred at room temperature for 5 hours. Aqueous ammonium chloridesolution was added to the reaction solution while stirring, and themixture was extracted twice with ethyl acetate. The combined organicphase was washed with water and saturated sodium chloride solution,dried over magnesium sulfate and concentrated under reduced pressure.The desired product crystallizes on treating the residue with diethylether. Yield: 19.2 g (66%) of a white solid. MS (API-ES, pos) m/z=386[M+H—H₂O]⁺

C)(S)-1-{5-Chloro-3-[5-(5,5-dimethyl[1,3]dioxan-2-yl)-2-methoxyphenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,mixture of diastereomers

Pyridine (0.24 ml, 3.0 mmol) and thionyl chloride (0.22 ml, 3.0 mmol)were added to a solution of the reaction product from stage 17B (1.00 g,2.5 mmol) in dichloromethane (10 ml) while cooling in ice, and themixture was stirred at 0° C. for 15 min. The reaction solution wasquenched with water while stirring, and the mixture was extracted withdichloromethane. The organic phase was washed with water and saturatedsodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. N,N-Diisopropylethylamine (1.14 ml, 6.5 mmol)and H-Pro-NMe₂ (0.34 g, 2.4 mmol, Bachem) were added to a solution ofthe 3-chlorooxindole intermediate obtained in this way indichloromethane (5 ml), and the reaction mixture was stirred at roomtemperature for 18 h. Sodium bicarbonate solution was added to thereaction mixture, which was then extracted several times withdichloromethane. The combined organic phase was washed with saturatedsodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel (mobile phase gradient 1-5% MeOH in dichloromethane). Yield:0.55 g (44%) of the desired product as mixture of diastereomers. MS(API-ES, pos) m/z=528 [M+H]⁺.

D)(S)-1-[5-Chloro-3-[5-(5,5-dimethyl[1,3]dioxan-2-yl)-2-methoxyphenyl]-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethyl-carboxamide,mixture of diastereomers

Sodium hydride (18 mg, 60% dispersion in mineral oil, 0.45 mmol) wasadded to a solution of the reaction product from stage 17C (200 mg, 0.38mmol) in DMF (5 ml) at 0° C. After 30 min, 4-methoxybenzenesulfonylchloride (82 mg, 0.40 mmol) was added to the reaction solution whilecooling in ice, and the mixture was stirred at room temperature for afurther 45 min. Sodium bicarbonate solution was cautiously added to themixture, which was then extracted twice with ethyl acetate. The combinedorganic phase was washed with water and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(mobile phase gradient 15-30% ethyl acetate in dichloromethane). Yield:150 mg (57%). MS (API-ES, pos) m/z=698 [M+H]⁺.

E)(S)-1-[5-Chloro-3-(5-formyl-2-methoxyphenyl)-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,levorotatory diastereomer

A solution of the reaction product from stage 17D (150 mg, 0.22 mmol) ina mixture of acetone (3 ml) and 2 N aqueous hydrochloric acid (3 ml) wasstirred at room temperature for 18 h. The reaction mixture was dilutedwith dichloromethane and neutralized by adding sodium bicarbonatesolution. The reaction mixture was extracted twice with dichloromethane.The organic phase was washed with water, dried over magnesium sulfateand concentrated under reduced pressure. The residue was purified bychromatography on silica gel (mobile phase gradient 10-30% ethyl acetatein dichloromethane). Yield: 63 mg (47%) of the levorotatory diastereomerwhich elutes earlier. MS (API-ES, pos) m/z=612 [M+H]⁺.

F)(S)-1-[5-Chloro-3-(5-dimethylaminomethyl-2-methoxyphenyl)-1-(4-ethoxybenzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

A solution of the reaction product from stage 17E (50 mg, 0.08 mmol) inTHF (1 ml) was mixed with a 2M solution of dimethylamine in THF (0.05ml, 0.1 mmol) and MP-triacetoxyborohydride-resin (Argonaut, 89 mg, f=2.3mmol/g, 0.20 mmol) and shaken at room temperature for 16 h. Thesolid-phase reagent was filtered off and washed with THF, and thesolution was concentrated under reduced pressure. The residue waspurified by preparative reversed phase HPLC (mobile phase: gradient from10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid). Yield: 37mg (61%); MS (API-ES, pos) m/z=641 [M+H]⁺.

The following Examples 18 to 33 were prepared in an analogous manner tothat described for Example 17 (see synthesis scheme 1):

Example 18(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=667 [M+H]⁺.

Example 19

(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-piperidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=681 [M+H]⁺.

Example 20(S)-1-{5-Chloro-1-(4-methoxybenzenesulfonyl)-3-[2-methoxy-5-(4-methylpiperazin-1-yl-methyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=696 [M+H]⁺.

Example 21(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-morpholin-4-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=683 [M+H]⁺. EXAMPLE 22

(S)-1-[5-Chloro-3-(5-{[(2-dimethylaminoethyl)methylamino]methyl}-2-methoxy-phenyl)-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=698 [M+H]⁺.

Example 23(S)-1-[5-Chloro-3-(5-{[(3-dimethylaminopropyl)methylamino]methyl}-2-methoxy-phenyl)-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=712 [M+H]⁺.

Example 24(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(5-dimethylaminomethyl-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=671 [M+H]*.

Example 25

(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-5-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=697 [M+H]⁺.

Example 26(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-5-piperidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidin-2-dimethylcarboxamidetrifluoroacetic acid salt

MS (API-ES, pos) m/z=711 [M+H]⁺.

Example 27(S)-1-{5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-[2-methoxy-5-(4-methyl-piperazin-1-ylmethyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=726 [M+H]⁺.

Example 28(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-5-morpholin-4-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=713 [M+H]⁺.

Example 29(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(5-{[(2-dimethylaminoethyl)-methylamino]methyl}-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=728 [M+H]⁺.

Example 30(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(5-{[(3-dimethylaminopropyl)-methylamino]methyl}-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=742 [M+H]⁺.

Example 31(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-4-{[(2-methoxy-ethyl)methylamino]methyl}phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=715 [M+H]⁺.

Example 32(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-{[(2-methoxyethyl)-methylamino]methyl}phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-dimethyl-carboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=685 [M+H]⁺.

Example 33(S)-1-[5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-methoxy-5-{[(2-methoxy-ethyl)methylamino]methyl}phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=715 [M+H]⁺.

Example 34(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[2-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt A)(4-Bromo-3-methoxyphenoxy)triisopropylsilane

A solution of 4-bromo-3-methoxyphenol (5.00 g, 24.6 mmol, Chontech) inTHF (50 ml) was added dropwise to a suspension of sodium hydride (1.08g, 60% dispersion in mineral oil, 27 mmol) in THF (100 ml) over 10 minwhile cooling in ice. The reaction mixture was stirred at 0° C. for 30min and then at room temperature for 60 min. Triisopropylsilyl chloridewas added dropwise to the phenolate solution, and the reaction mixturewas stirred at room temperature for 60 min. Water was added to themixture while cooling in ice, and it was then extracted several timeswith ethyl acetate. The combined organic phase was washed with saturatedsodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. Purification by chromatography on silica gel(mobile phase: 2-10% gradient of ethyl acetate in dichloromethane)afforded 8.67 g (98%) of the desired product.

B)5-Chloro-3-hydroxy-3-(2-methoxy-4-triisopropylsilanyloxyphenyl)-1,3-dihydroindol-2-one

A solution of n-butyllithium in hexane (1.6 m, 19.6 ml, 31.4 mmol) wasslowly added dropwise to a solution of(4-bromo-3-methoxyphenoxy)triisopropylsilane (8.67 g, 24.1 mmol) in THF(100 ml) at −15° C. After 15 min, a solution of 5-chloroisatin sodiumsalt [prepared by treating a solution of 5-chloroisatin (3.65 g, 20.1mmol) in THF with one equivalent of sodium hydride at 0° C. for one h]was added dropwise to the solution of the organolithium species. Thereaction mixture was allowed to warm to room temperature and was stirredfor a further hour. Aqueous ammonium chloride solution was added to thereaction solution while stirring, and the mixture was extracted withethyl acetate. The combined organic phase was washed with water andsaturated sodium chloride solution, dried over magnesium sulfate andconcentrated under reduced pressure. Purification by chromatography onsilica gel (mobile phase 10-30% gradient of ethyl acetate indichloromethane) afforded 3.8 g (41%) of the desired adduct.

C)(S)-1-[5-Chloro-3-(2-methoxy-4-triisopropylsilanyloxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,levorotatory diastereomer

Pyridine (0.53 ml, 6.5 mmol) and thionyl chloride (0.47 ml, 6.5 mmol)were added to a solution of the reaction product from stage 34B (2.50 g,5.4 mmol) in dichloromethane (20 ml) while cooling in ice, and themixture was stirred at 0° C. for 15 min. The reaction solution wasquenched with water while stirring, and the mixture was extracted withdichloromethane. The organic phase was washed with water and saturatedsodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. N,N-Diisopropylethylamine (3.0 ml, 17.0 mmol)and (S)-pyrrolidine-2-dimethylcarboxamide (0.89 g, 6.2 mmol, Bachem)were added to a solution of the 3-chlorooxindole intermediate obtainedin this way in dichloromethane (10 ml), and the reaction mixture wasstirred at room temperature for 18 h. The reaction mixture was mixedwith water and extracted several times with dichloromethane. Thecombined organic phase was washed with saturated sodium chloridesolution, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(mobile phase gradient 20-50% ethyl acetate in dichloromethane). Yield:0.83 g (22%) of the levorotatory diastereomer which elutes earlier. MS(API-ES, pos) m/z=586 [M+H]⁺; [α]_(D)-150 (c 0.1, CHCl₃, 20° C.)

D)(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-4-triisopropylsilanyl-oxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-pyrrolidine-2-dimethylcarboxamide

Sodium hydride (13 mg, 60% dispersion in mineral oil, 0.33 mmol) wasadded to a solution of the reaction product from stage 34C (160 mg, 0.27mmol) in DMF (2 ml) at 0° C. After 30 min, 4-cyanobenzenesulfonylchloride (66 mg, 0.33 mmol) was added to the reaction solution whilecooling in ice, and the mixture was stirred at room temperature for afurther 45 min. Sodium bicarbonate solution was cautiously added to themixture, which was then extracted twice with ethyl acetate. The combinedorganic phase was washed with water and saturated sodium chloridesolution, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(mobile phase gradient 40-100% ethyl acetate in dichloromethane). Yield:148 mg (72%).

E)(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(4-hydroxy-2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

A solution of tetra-n-butylammonium fluoride in THF (1.0 m, 10 ml, 10mmol) was added to a solution of the reaction product from stage 34D(574 mg, 0.76 mmol) in THF (10 ml) at 0° C. After 30 min, water wasadded to the mixture, which was then extracted several times with ethylacetate. The combined organic phase was washed with saturated sodiumchloride solution, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by chromatography on silicagel (mobile phase gradient 70-100% ethyl acetate in dichloromethane).Yield: 376 mg (83%). MS (API-ES, pos) m/z=595 [M+H]⁺.

F)(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[2-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

The reaction product from stage 34E (35 mg, 0.06 mmol) was heatedtogether with 1-(2-chloroethyl)pyrrolidine hydrochloride (19 mg, 0.12mmol) and finely powdered potassium carbonate (24 mg, 0.18 mmol) in DMF(0.5 ml) in a microwave (100° C., 150 W). The filtrate after filtrationwas concentrated and purified by preparative reversed phase HPLC. Yield:13 mg; MS (API-ES, pos) m/z=692 [M+H]⁺.

The following Examples 35 to 39 were prepared in an analogous manner tothat described for Example 34 (see synthesis scheme 2):

Example 35(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[4-(2-dimethylaminoethoxy)-2-methoxyphenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=666 [M+H]⁺.

Example 36(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[2-methoxy-4-(2-morpholin-4-yl-ethoxy)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=708 [M+H]⁺.

Example 37(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[2-methoxy-4-(3-piperidin-1-yl-propoxy)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=720 [M+H]⁺.

Example 38(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[4-(3-dimethylaminopropoxy)-2-methoxyphenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=680 [M+H]⁺.

Example 39(S)-1-(5-Chloro-1-(4-cyanobenzenesulfonyl)-3-{2-methoxy-4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-2-oxo-2,3-dihydro-1H-indol-3-yl)pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=735 [M+H]⁺.

In addition, Examples 40 to 68 mentioned below can be prepared in ananalogous manner as shown in synthesis scheme 1.

Example 40(S)-1-[5-Chloro-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidin-2-dimethylcarboxamideExample 41(S)-1-[5-Chloro-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-1-(5-methylpyridine-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 42(S)-1-[5-Chloro-1-(5-chloropyridin-2-sulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 43(S)-1-[5-Chloro-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 44(S)-1-[(5-Chloro-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 45(S)-1-[5-Chloro-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 46(2S,4R)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-dimethyl-carboxamideExample 47(2S,4R)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoropyrrolidine-2-dimethyl-carboxamideExample 48(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]piperidine-2-dimethylcarboxamideExample 49(S)-2-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N,N-dimethylpropionamideExample 50(S)-1-[5-Cyano-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 51(S)-1-[5-Cyano-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-1-(5-methylpyridin-2-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 52(S)-1-[5-Cyano-1-(5-chloropyridine-2-sulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 53(S)-1-[5-Cyano-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(thiophene-2-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 54(S)-1-[(5-Cyano-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(thiophene-3-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 55(S)-1-[5-Cyano-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-1-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 56(S)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidin-2-dimethylcarboxamideExample 57(2S,4R)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxypyrrolidine-2-dimethyl-carboxamideExample 58(2S,4R)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-fluoropyrrolidine-2-dimethyl-carboxamideExample 59(S)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]piperidine-2-dimethylcarboxamideExample 60(S)-2-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N,N-dimethylpropionamideExample 61(S)-1-[5-Cyano-3-(5-dimethylaminomethyl-2-methoxyphenyl)-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 62(S)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-pyrrolidin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 63(S)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-piperidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 64(S)-1-{5-Cyano-1-(4-methoxybenzenesulfonyl)-3-[2-methoxy-5-(4-methylpiperazin-1-yl-methyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamideExample 65(S)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-morpholin-4-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 66(S)-1-[5-Cyano-3-(5-{[(2-dimethylaminoethyl)methylamino]methyl}-2-methoxy-phenyl)-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 67(S)-1-[5-Cyano-3-(5-{[(3-dimethylaminopropyl)methylamino]methyl}-2-methoxy-phenyl)-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamideExample 68(S)-1-[5-Cyano-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-5-{[(2-methoxy-ethyl)methylamino]methyl}phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidin-2-dimethylcarboxamide

In addition, the following Examples 69 to 102 can be prepared in ananalogous manner to that described for Examples 2 and 17 (synthesisscheme 1):

Example 69(S)-1-{5-Chloro-1-(4-methoxybenzenesulfonyl)-3-[2-methoxy-4-(4-methylpiperazin-1-ylmethyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=696 [M+H]⁺.

Example 70(S)-1-[5-Chloro-3-(4-dimethylaminomethyl-2-methoxyphenyl)-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=641 [M+H]⁺.

Example 71(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-morpholin-4-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=683 [M+H]⁺.

Example 72(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(4-dimethylaminomethyl-2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=636 [M+H]⁺.

Example 73(S)-1-[5-Chloro-3-(4-dimethylaminomethyl-2-methoxyphenyl)-1-(4-fluorobenzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=629 [M+H]⁺.

Example 74(S)-1-{5-Chloro-1-(4-fluorobenzenesulfonyl)-3-[2-methoxy-4-(4-methylpiperazin-1-yl-methyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=684 [M+H]⁺.

Example 75(S)-1-[3-(4-Aminomethyl-2-methoxyphenyl)-5-chloro-1-(4-fluorobenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=602 [M+H]⁺.

Example 76(S)-1-[3-(4-Aminomethyl-2-methoxyphenyl)-5-chloro-1-(4-cyanobenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=609 [M+H]⁺.

Example 77(S)-1-[5-Chloro-1-(4-fluorobenzenesulfonyl)-3-(2-methoxy-4-morpholin-4-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=671 [M+H]⁺.

Example 78(S)-1-[5-Chloro-1-(4-fluorobenzenesulfonyl)-3-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=670 [M+H]⁺.

Example 79(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-piperazin-1-yl-methylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=682 [M+H]⁺.

Example 80(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[2-methoxy-4-(4-methylpiperazin-1-ylmethyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-carboxylicacid dimethylamide, trifluoroacetic acid salt

MS (API-ES, pos) m/z=691 [M+H]⁺.

Example 81(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-4-morpholin-4-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=678 [M+H]⁺.

Example 82(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=677 [M+H]⁺.

Example 83(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-piperidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=681 [M+H]⁺.

Example 84(S)-1-[5-Chloro-3-{4-[(ethylmethylamino)methyl]-2-methoxyphenyl}-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=655 [M+H]⁺.

Example 85(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-propylaminomethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=655 [M+H]⁺.

Example 86(S)-1-[5-Chloro-3-(4-diethylaminomethyl-2-methoxyphenyl)-1-(4-methoxybenzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=669 [M+H]⁺.

Example 87(S)-1-[3-(4-Azetidin-1-ylmethyl-2-methoxyphenyl)-5-chloro-1-(4-methoxybenzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=653 [M+H]⁺.

Example 88(S)-1-[5-Chloro-3-{4-[(isopropylmethylamino)methyl]-2-methoxyphenyl}-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=669 [M+H]⁺.

Example 89(S)-1-[5-Chloro-1-(4-methoxybenzenesulfonyl)-3-(2-methoxy-4-{[(2-methoxyethyl)-methylamino]methyl}phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethyl-carboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=685 [M+H]⁺.

Example 90(S)-1-[3-(4-Dimethylaminomethyl-2-methoxyphenyl)-1-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=607 [M+H]⁺.

Example 91(S)-1-[1-(4-Methoxybenzenesulfonyl)-3-(2-methoxy-4-pyrrolidin-1-ylmethylphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=633 [M+H]⁺.

Example 92(S)-1-{1-(4-Methoxybenzenesulfonyl)-3-[2-methoxy-4-(4-methylpiperazin-1-yl-methyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}-pyrrolidine-2-carboxylicacid dimethylamide, trifluoroacetic acid salt

MS (API-ES, pos) m/z=662 [M+H]⁺.

Example 93(S)-1-[5-Chloro-3-(4-ethylaminomethyl-2-methoxyphenyl)-1-(4-methoxybenzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=641 [M+H]⁺.

Example 94(S)-1-[5-Chloro-3-[4-(isopropylaminomethyl)-2-methoxyphenyl]-1-(4-methoxybenzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=655 [M+H]⁺.

Example 95(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(5-dimethylaminomethyl-2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=636 [M+H]⁺.

Example 96(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-5-pyrrolidin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide

MS (API-ES, pos) m/z=662 [M+H]⁺.

Example 97(S)-1-{5-Chloro-1-(4-cyanobenzenesulfonyl)-3-[2-methoxy-5-(4-methylpiperazin-1-yl-methyl)phenyl]-2-oxo-2,3-dihydro-1H-indol-3-yl}pyrrolidine-2-carboxylicacid dimethylamide, trifluoroacetic acid salt

MS (API-ES, pos) m/z=691 [M+H]⁺.

Example 98(S)-1-[5-Chloro-3-(5-dimethylaminomethyl-2-methoxyphenyl)-1-(4-fluorobenzene-sulfonyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=629 [M+H]⁺.

Example 99(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=677 [M+H]⁺.

Example 100(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-5-propylaminomethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=650 [M+H]⁺.

Example 101(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(5-isopropylaminomethyl-2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=650 [M+H]⁺.

Example 102(S)-1-[5-Chloro-1-(4-cyanobenzenesulfonyl)-3-(2-methoxy-5-methylaminomethyl-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]pyrrolidine-2-dimethylcarboxamide,trifluoroacetic acid salt

MS (API-ES, pos) m/z=622 [M+H]⁺.

Methods for Determining the Biological Activity Vasopressin V1b ReceptorBinding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO(dimethyl sulfoxide) and further diluted to 5×10⁻⁴ M to 5×10⁻⁹ M inDMSO. This series of DMSO predilutions was diluted 1:10 with assaybuffer. The substance concentration was again diluted 1:5 in the assaymixture (2% DMSO in the mixture).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone3H2) were harvested and homogenized in 50 mM Tris-HCl and in thepresence of protease inhibitors (Roche complete Mini # 1836170) with aPolytron homogenizer at a medium setting for 2×10 seconds andsubsequently centrifuged at 40 000×g for 1 h. The membrane pellet wasagain homogenized and centrifuged as described and then taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by a method based on that of Tahara etal. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)). Theincubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1b receptors(cell line hV1b_(—)3H2_CHO) were incubated with 1.5 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 uM AVP(Bachem # H1780). All determinations were carried out as triplicatedeterminations. After incubation (60 minutes at room temperature), thefree radioligand was removed by vacuum filtration (Skatron cellharvester 7000) through Whatman GF/B glass fiber filter mats, and thefilters were transferred into scintillation vials. The liquidscintillation measurement took place in a Tricarb model 2000 or 2200CAinstrument (Packard). Conversion of the measured cpm into dpm wascarried out with the aid of a standard quench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant hV2 receptors is 0.4 nMand was used to determine the Ki value.

Vasopressin V1a Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.These DMSO solutions were further diluted in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone5) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini # 1836170) with a Polytronhomogenizer at a medium setting for 2×10 seconds and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and then taken up in 50 mMTris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by a method based on that of Tahara etal. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (20 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1a receptors(cell line hV1a-5-CHO) were incubated with 0.04 nM ¹²⁵I-AVP(8-Arg-vasopressin, NEX 128) in incubation buffer (50 mM Tris, 10 mMMgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasingconcentrations of test substance (displacement experiment). Thenonspecific binding was determined with 1 μM AVP (Bachem # H1780).Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas removed by vacuum filtration (Skatron cell harvester 7000) throughWhatman GF/B glass fiber filter mats, and the filters were transferredinto scintillation vials. The liquid scintillation measurement tookplace in a Tricarb model 2000 or 2200CA instrument (Packard). Conversionof the measured cpm into dpm was carried out with the aid of a standardquench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors wasdetermined in saturation experiments. A Kd of 1.33 nM was used todetermine the Ki value.

Vasopressin V2 Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.These DMSO solutions were further diluted in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V2 receptor (clone23) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini # 1836170) with a Polytronhomogenizer at a medium setting for 2×10 seconds and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and then taken up in 50 mMTris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by a method based on that of Tahara etal. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V2 receptors (cellline hV2-23-CHO) were incubated with 1-2 nM ³H-AVP (8-Arg-vasopressin,PerkinElmer #18479) in incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1%BSA, pH 7.4) (total binding) or additionally with increasingconcentrations of test substance (displacement experiment). Thenonspecific binding was determined with 1 μM AVP (Bachem # H1780).Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas removed by vacuum filtration (Skatron cell harvester 7000) throughWhatman GF/B glass fiber filter mats, and the filters were transferredinto scintillation vials. The liquid scintillation measurement tookplace in a Tricarb model 2000 or 2200CA instrument (Packard). Conversionof the measured cpm into dpm was carried out with the aid of a standardquench series.

Evaluation:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant hV2 receptors is 2.4 nMand was used to determine the Ki value.

Oxytocin Receptor Binding Assay Substances:

The substances were dissolved in a concentration of 10⁻² m in DMSO anddiluted with incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH7.4).

Cell Preparation:

Confluent HEK-293 cells with transiently expressing recombinant humanoxytocin receptors were centrifuged at 750×g and at room temperature for5 minutes. The residue was taken up in ice-cold lysis buffer (50 mMTris-HCl, 10% glycerol, pH7.4 and Roche Complete Protease Inhibitor) andsubjected to an osmotic shock at 4° C. for 20 minutes. The lysed cellswere then centrifuged at 750×g and at 4° C. for 20 minutes, the residuewas taken up in incubation buffer, and aliquots of 10⁷ cells/ml wereprepared. The aliquots were frozen at −80° C. until used.

Binding Assay:

On the day of the experiment, the cells were thawed, diluted withincubation buffer and homogenized using a Multipette Combitip(Eppendorf, Hamburg). The reaction mixture of 0.250 ml was composed of 2to 5×10⁴ recombinant cells, 3-4 nM ³H-oxytocin (PerkinElmer, NET 858) inthe presence of test substance (inhibition plot) or only incubationbuffer (total binding). The nonspecific binding was determined with 10⁻⁶M oxytocin (Bachem AG, H2510). Determinations in triplicate were set up.Bound and free radioligand were separated by filtration under vacuumwith Whatmann GF/B glass fiber filters using a Skatron cell harvester7000. The bound radioactivity was determined by liquid scintillationmeasurement in a Tricarb beta counter, model 2000 or 2200CA (Packard).

Evaluation:

The binding parameters were calculated by nonlinear regression analysis(SAS), in analogy to the LIGAND program of Munson and Rodbard(Analytical Biochem 1980; 107: 220-239). The Kd of ³H-oxytocin for therecombinant hOT receptors is 7.6 nM and was used to determine the Kivalue.

Effect on Vasopressin-Induced Calcium Increase in Cells Having a ClonedHuman Vasopressin Receptor

The functional activity of the test substances was investigated onCHO-K1 cells which were stably transfected with the human V1b receptor.50 000 cells were seeded in each well of a microtiter plate with 96wells and incubated in culture medium in a saturated water vaporatmosphere with 5% CO₂ at 37° C. overnight. The culture medium consistedof DMEM/Nut Mix F12 with Glutamax I (from Invitrogen), 10% fetal calfserum, 100 units/ml penicillin, 100 μg/ml streptomycin and 800 μg/mlGeneticin. The following day, the cells were washed with culture mediumand loaded with a fluorescent dye for calcium in accordance with themanufacturer's statements (Ca⁺⁺-Plus-Assay Kit, Molecular Devices). Thecells were loaded in the presence of probenzide (1 vol %). The testsubstances were diluted with culture medium (final concentration 10⁻¹⁰to 10⁻⁵M) and incubated with the dye-loaded cells at room temperaturefor 15 minutes. The Arg-vasopressin (10⁻⁸M) was then added and themaximum fluorescence signal was determined using a FLIPR-96 measuringinstrument (Molecular Devices). Concentration-effect plots wereconstructed using nonlinear regression algorithms (GraphPad Prism 3.0).Kb values were calculated from IC50 values by the method of Cheng andPrusoff (Kb=IC50/1+L/EC50).

The affinities of the compounds (I) of the invention for the humanvasopressin V1b receptor were measured in accordance with the aboveassays, and the affinity constants (Ki) were determined. Table 1 belowdetails the V1b receptor affinity of selected compounds (+++ means <1nM, ++ means 1-10 nM and + means 10-100 nM).

TABLE 1 Example V1b Ki 1 +++ 2 +++ 3 ++ 4 +++ 5 +++ 6 + 7 ++ 8 ++ 9 ++10 + 11 + 12 ++ 13 ++ 14 ++ 15 +++ 16 ++ 17 +++ 18 +++ 19 +++ 20 +++ 21+++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ 28 ++ 29 +++ 30 +++ 31 ++32 +++ 33 +++ 69 +++ 70 +++ 71 +++ 72 ++ 73 ++ 74 +++ 75 + 76 ++ 77 + 78+++ 79 +++ 80 +++ 81 ++ 82 +++ 83 +++ 84 +++ 85 +++ 86 +++ 87 +++ 88 +++89 +++ 90 + 91 ++ 92 ++ 93 +++ 94 +++ 95 ++ 96 +++ 97 +++ 98 ++ 99 +++100 +++ 101 +++ 102 ++

It is additionally possible in accordance with the above assays todetermine the affinities for further vasopressin receptors or theirsubtypes such as, for example, V1a and V2, and the oxytocin (OT)receptor. The quotients obtainable thereby for the corresponding Kivalues, i.e. “Ki(V1a)/Ki(V1b)”, “Ki(V2)/Ki(v1b)” and/or “Ki(OT)Ki(V1b)”,may serve as a measure of a possible selectivity of the compounds of theinvention in relation to a particular vasopressin or oxytocin receptoror one of their subtypes such as, for example, V1b.

The compounds of the invention showed a surprisingly high affinity forthe human V1b receptor, frequently less than or equal to 1 nM and insome cases even less than or equal to 0.1 nM. A number of compounds ofthe invention act as functional antagonist of the human vasopressin V1breceptor, e.g. Example 2. Because of the greatly raised affinity of thecompounds of the invention for the human V1b receptor, they will eliciteven at relatively low concentrations/effective levels the therapeuticeffects mediated by V1b receptors. Low effective levels are generallydesired because the probability of side effects which are not elicitedby the interaction with human V1b receptors is lower thereby.

1. A compound of the formula (I),

in which A is an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic radical which consists of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen atoms and/or 0, 1 or 2 oxygen atoms and/or 0, 1 or 2 sulfur atoms, and which is substituted by the radical R_(A) ¹ and may besides be additionally substituted by 1, 2 or 3 radicals R_(A) ¹¹, R_(A) ¹² and/or R_(A) ¹³ which are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, OCHF₂, CO—NH₂, CO—NH(C₁-C₄-alkyl), CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NHCHO, NH—CO—NH₂, NH—CO(C₁-C₄-alkyl), NO₂, OH, O—C₁-C₄-alkyl, O—C₀-C_(a)-alkylene-phenyl, phenyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl, in which R_(A) ¹ is R_(A) ²—(C₁-C₄-alkylene)-R_(A) ⁴, R_(A) ² is selected from the group consisting of (C₀-C₄-alkylene-O, (C₀-C₄-alkylene)-NR_(A) ⁵, (C₀-C₄-alkylene)-S, (C₀-C₄-alkylene)-SO, (C₀-C₄-alkylene)-SO₂, (C₀-C₄-alkylene)-CO, (C₀-C₄-alkylene)-NR_(A) ⁵—CO, (C₀-C₄-alkylene)-CO—NR_(A) ⁵, (C₀-C₄-alkylene)-CO—O, (C₀-C₄-alkylene)-NR_(A) ⁵—SO₂, (C₀-C₄-alkylene)-SO₂—N NR_(A) ⁵, (C₀-C₄-alkylene)-NR_(A) ⁵—CO—NR_(A) ⁶, (C₀-C₄-alkylene)-O—CO—NR_(A) ⁵, (C₀-C₄-alkylene)-NR_(A) ⁵—CO—O and single bond, R_(A) ⁴ is selected from the group consisting of NH₂, (C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH(C₁-C₄-alkylene-O—C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkylene-O—C₁-C₄-alkyl), NH—CHO, N(C₁-C₄-alkyl)-CHO, NH—CO—NH₂, N(C₁-C₄-alkyl)-CO—NH₂, NH—CO—C₁-C₄-alkyl, alkyl, NH—SO₂—C₁-C₄-alkyl, N(C₁-C₄-alkyl)-SO₂—C₁-C₄-alkyl and ring R_(A) ⁸, R_(A) ⁵, R_(A) ⁶, R_(A) ⁹ are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl; R_(A) ⁸ is selected from the group consisting of the respective individual radicals

B is an aromatic, heteroaromatic, partly aromatic or partly heteroaromatic mono- or bicyclic radical which consists of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 0, 1, 2, 3 or 4 nitrogen atoms and/or 0, 1 or 2 oxygen atoms and/or 0, 1 or 2 sulfur atoms, and which may be substituted by 1, 2 or 3 radicals R_(B) ¹, R_(B) ² and/or R_(B) ³, where R_(B) ¹, R_(B) ² and R_(B) ³ are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, OCHF₂, CO—NH₂, CO—NH(C₁-C₄-alkyl), CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH—CHO, NH—CO—NH₂, NH—CO—C₁-C₄-alkyl, NO₂, OH, O—C₁-C₄-alkyl, O—C₀-C₄-alkylenephenyl, phenyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl; R¹ is selected from the group consisting of hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, OCHF₂, CO—NH₂, CO—NH(C₁-C₄-alkyl), CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH—CHO, NH—CO—NH₂, NH—CO—C₁-C₄-alkyl, NO₂, OH, O—C₁-C₄-alkyl, O—C₀-C₄-alkylenephenyl, phenyl, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl, R² is selected from the group consisting of hydrogen, C₁-C₄-alkyl, O—C₁-C₄-alkyl, chlorine and fluorine, Y is a radical

in which R_(Y) ¹ is selected from the group consisting of hydrogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl; R_(Y) ² is selected from the group consisting of hydrogen; phenyl; phenyl substituted by 1, 2, 3, 4 or 5 radicals R_(Ph) ¹ R_(Ph) ², R_(Ph) ³, R_(Ph) ⁴ and/or R_(Ph) ⁵ which are selected independently of one another from the group consisting of hydrogen, halogen, C₁-C₆-alkyl and C₁-C₆-alkoxy; C₁-C₆-cycloalkyl and C₁-C₆-haloalkyl; in which R_(Y) ¹ and R_(Y) ² may also form together with the atoms to which they are bonded a 4-, 5-, 6- or 7-membered, saturated or unsaturated ring which may, instead of a ring C atom, also include a heteroatom selected from the group consisting of O, S and NR_(Y) ⁵ as further ring member, where R_(Y) ⁵ may independent of its respective occurrence be hydrogen, C₁-C₄-alkyl or CO—C₁-C₄-alkyl, and where the ring may have one or two substituents R_(Y) ⁶ and R_(Y) ⁷ which are selected independently of one another and independent of their respective occurrence from the group consisting of the radicals hydrogen, chlorine, bromine, iodine, fluorine, CN, CF₃, OCF₃, OCHF₂, CO—NH₂, CO—NH(C₁-C₄-alkyl), CO—N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), NH—CHO, NH—CO—NH₂, NH—CO—C₁-C₄-alkyl, OH, O—C₁-C₄-alkyl, O—CO—C₁-C₄-alkyl, O—(CH₂)₀-₂-phenyl, phenyl, C₁-C₆-alkyl, or R_(Y) ⁶ and R_(Y) ⁷ may also independent of their respective occurrence form together with the C atoms to which they are bonded a fused phenyl ring or a fused 5- or 6-membered, aromatic heterocycle which, besides C atoms, includes as ring members 1, 2, 3 or 4 identical or different heteroatoms as ring members which may be selected independently of one another from the group consisting of nitrogen, oxygen and sulfur, R_(Y) ³ is selected from the group consisting of hydrogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl; R_(Y) ⁴ is selected from the group consisting of hydrogen, CO—NR_(Y) ²¹R_(Y) ²², CO—C₁-C₄-alkyl, COOH and CO—O—C₁-C₄-alkyl, R_(Y) ²¹, R_(Y) ²² are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, C₁-C₄-alkyl and C₁-C₄-haloalkyl; or R_(Y) ²¹ and R_(Y) ²² may also independent of their respective occurrence form together with the nitrogen atom to which they are bonded a 4-, 5- or 6-membered, saturated or wholly or partly unsaturated N-heterocyclic ring.
 2. A compound of the formula (I) of claim 1, in which A is an aromatic or heteroaromatic monocyclic radical having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members, which may besides comprise additionally 0, 1, 2 or 3 identical or different heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and 20 sulfur, as ring members, and is substituted by the radical R_(A) ¹ and may besides be substituted by one, two or three radicals R_(A) ¹¹, R_(A) ¹² and/or R_(A) ¹³ which are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, chlorine, fluorine, O—C₁-C₄-alkyl, C₁-C₄-alkyl and C₁-C₄-haloalkyl, in which R_(A) ¹ is R_(A) ²—(C₁-C₄-alkylene)-R_(A) ⁴; R_(A) ² is selected from the group consisting of (C₀-C₄-alkylene)-O, (C₀-C₄-alkylene)-NR_(A) ⁵, (C₀-C₄-alkylene)-S, (C₀-C₄-alkylene)-SO, (C₀-C₄-alkylene)-SO₂, (C₀-C₄-alkylene)-CO, (C₀-C₄-alkylene)-NR_(A) ⁵—CO, (C₀-C₄-alkylene)-CO—NR_(A) ⁵, (C₀-C₄-alkylene)-CO—O and single bond; R_(A) ⁴ is selected from the group consisting of NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkylene-O—C₁-C₄-alkyl) and ring R_(A) ⁸, R_(A) ⁵, R_(A) ⁹ are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen and C₁-C₄-alkyl; R_(A) ⁸ is selected independent of its respective occurrence from the group consisting of the respective individual radicals

B is an aromatic or heteroaromatic mono- or bicyclic radical having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members, which may additionally comprise 1, 2 or 3 identical or different heteroatoms selected independently of one another from the group consisting of nitrogen, oxygen and sulfur as ring members, and which may be substituted by one, two or three radicals R_(B)I, R_(B)2 and/or R_(B)3, where R_(B1), R_(B)2 and R_(B)3 are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, chlorine, bromine, fluorine, CN, CF₃, OCF₃, OCHF₂, O—C₁-C₄-alkyl, C₁-C₄-alkyl and C₁-C₄-haloalkyl; R¹ is selected from the group consisting of hydrogen, bromine, chlorine, fluorine, CN, CF₃, OCF₃, O—C₁-C₄-alkyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl and C₂-C₄-alkynyl, R² is selected from the group consisting of hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, O—C₁-C₄-alkyl, chlorine and fluorine, Y is a radical

in which R_(Y) ¹ is selected from the group consisting of hydrogen and C₁-C₄-alkyl; R_(Y) ² is selected from the group consisting of hydrogen, phenyl, C,-C₆-alkyl, and C₃-C₇-cycloalkyl, in which R_(Y) ¹ and R_(Y) ² may also form together with the atoms to which they are bonded a 4-, 5-, 6- or 7-membered, saturated or unsaturated ring which may, instead of a C atom as ring member, also include a hetero-atom selected from the group consisting of O and NR_(Y) ⁵, as further ring member, where R_(Y) ⁵ may independent of its respective occurrence be hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl or CO—C₁-C₄-alkyl, and where the ring may have one or two substituents R_(Y) ⁶ and/or R_(Y) ⁷ which are selected independently of one another and independent of their respective occurrence from the group consisting of the radicals hydrogen, fluorine, CN, OH, O—C₁-C₄-alkyl, O—CO—C₁-C₄-alkyl, O—(CH₂)₀₋₂-phenyl, phenyl and C₁-C₄-alkyl; or R_(Y) ⁶ and R_(Y) ⁷ may independent of their respective occurrence also form together with the C atoms to which they are bonded a fused phenyl ring (benzo ring); R_(Y) ³ is selected from the group consisting of hydrogen and methyl, R_(Y) ⁴ is selected from the group consisting of CO—NR_(Y) ²¹R_(Y) ²², CO—C₁-C₄-alkyl and CO—O—C₁-C₄-alkyl, R_(Y) ²¹, R_(Y) ²² are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen and C₁-C₄-alkyl; or R_(Y) ²¹ and R_(Y) ²² may independent of their respective occurrence also form together with the nitrogen atom to which they are bonded a 4-, 5- or 6-membered, saturated or unsaturated N-heterocyclic ring, the tautomeric, enantiomeric and diastereomeric forms thereof, and the prodrugs thereof, and the physiologically tolerated salts of said compound.
 3. A compound of the formula I of claim 1, in which A is a cyclic radical which is selected from the group consisting of phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, and which is substituted by the radical R_(A) ¹ and may besides be additionally substituted by one or two radicals R_(A) ¹¹ and/or R_(A) ¹² which are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, chlorine, methoxy, ethoxy, propoxy, methyl, ethyl and propyl; in which R_(A) ¹ is R_(A) ²—(C₁-C₄-alkylene)-R_(A) ⁴, in which R_(A) ² is selected from the group consisting of O, CH₂—O, NR_(A) ⁵, CH₂—NR_(A) ⁵, NR_(A) ⁵—CO, CH₂—NR_(A) ⁵—CO and a single bond; RA4 is selected from the group consisting of NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkyl), N(C₁-C₄-alkyl)(C₁-C₄-alkylene-O—C₁-C₄-alkyl) and ring R_(A) ⁸; R_(A) ⁵, R_(A) ⁹ are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen and C₁-C₄-alkyl; R_(A) ⁸ is selected from the group consisting of the respective individual radicals

B is an aromatic or heteroaromatic mono- or bicyclic radical having 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms as ring members, which may comprise 1, 2 or 3 identical or different heteroatoms selected independently of one another from the group consisting of nitrogen, oxygen and sulfur as ring member, and which may be substituted by one or two radicals R_(B) ¹ and/or R_(B) ², where R_(B) ¹ and R_(B) ² are selected independently of one another from the group consisting of hydrogen, chlorine, fluorine, CN, O—C₁-C₄-alkyl and C₁-C₄-alkyl; R¹ is selected from the group consisting of hydrogen, chlorine, fluorine, CN, methoxy and methyl; R2 is selected from the group consisting of hydrogen, chlorine and methyl; Y is a radical

in which R_(Y) ¹ is selected from the group consisting of hydrogen and C₁-C₄-alkyl; R_(Y) ² is selected from the group consisting of hydrogen, phenyl and C₁-C₄-alkyl; where R_(Y) ¹ and R_(Y) ² may also form together with the atoms to which they are bonded a 5- or 6-membered, saturated or unsaturated ring which, instead of a C atom as ring member, may also include a heteroatom selected from the group consisting of O and NR_(Y) ⁵ as further ring member, where R_(Y) ⁵ may independent of its respective occurrence be hydrogen, C₁-C₄-alkyl, or CO—C₁-C₄-alkyl, and where the ring may have one or two substituents R_(Y) ⁶ and/or R y⁷ which are selected independently of one another and independent of their respective occurrence from the group consisting of the radicals hydrogen, fluorine, OH and O—C₁-C₄-alkyl, or R_(Y) ⁶ and R_(Y) ⁷ may independent of their respective occurrence also form together with the C atoms to which they are bonded a fused phenyl ring (benzo ring); R_(Y) ³ is selected from the group consisting of hydrogen and methyl; R_(Y) ⁴ is CO—NR_(Y) ²¹R_(Y) ²², in which R_(Y) ²¹, R_(Y) ²² are selected independently of one another from the group consisting of hydrogen and C₁-C₄-alkyl; or R_(Y) ²¹ and R_(Y) ²² may independent of their respective occurrence also form together with the nitrogen atom to which they are bonded a 4-, 5- or 6-membered, saturated or unsaturated N-heterocyclic ring; the tautomeric, enantiomeric and diastereomeric forms thereof, and the prodrugs thereof, and the physiologically tolerated salts of said compound.
 4. A compound of the formula (I) of claim 1, in which A is a radical selected from the group consisting of the respective individual radicals

in which R_(A) ¹¹ is selected independent of its respective occurrence from the group consisting of hydrogen, chlorine, methoxy and ethoxy; R_(A) ¹ is a radical selected from the group consisting of the respective individual radicals

B is a cyclic radical selected from the group consisting of phenyl, pyridyl, thienyl and quinolinyl, which may in each case be substituted by 1 or 2 radicals R_(B) ¹ and/or R_(B) ², where R_(B) ¹ and R_(B) ² are selected independently of one another from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy; R¹ is selected from the group consisting of hydrogen, chlorine, fluorine, CN, methoxy and methyl; R² is selected from the group consisting of hydrogen and chlorine; Y is a radical selected from the group consisting of the respective individual radicals.

R_(Y) ⁴ is CO—NR_(Y) ²¹R_(Y) ²², where R_(Y) ²¹ and R_(Y) ²² are selected independently of one another from the group consisting of hydrogen, methyl and ethyl; or R_(Y) ²¹ and R_(Y) ²² may independent of their respective occurrence also form together with the nitrogen atom to which they are bonded a 4-, 5- or 6-membered, saturated or unsaturated or partly unsaturated N-heterocyclic ring; R_(Y) ⁵ is selected from the group consisting of the radicals hydrogen, C₁-C₄-alkyl, and CO—C₁-C₄-alkyl R_(Y) ⁶ is selected from the group consisting of the radicals hydrogen, fluorine, OH and O—C₁-C₄-alkyl, the tautomeric, enantiomeric and diastereomeric forms thereof, and the prodrugs thereof, and the physiologically tolerated salts of said compound.
 5. A compound of the formula (I) of claim 1, in which A is selected from the group consisting of the respective individual radicals

R_(A) ¹ is a radical selected independent of its respective occurrence from the group consisting of the respective individual radicals

B is a cyclic radical selected from the group consisting of the respective individual radicals

in which R_(B) ¹ and R_(B) ² are selected independently of one another and independent of their respective occurrence from the group consisting of hydrogen, chlorine, fluorine, CN, methyl and methoxy; R¹ is selected from the group consisting of chlorine, methoxy and CN; R2 is hydrogen; Y is selected from the group consisting of the respective individual radicals

the tautomeric, enantiomeric and diastereomeric forms thereof, and the prodrugs thereof, and the physiologically tolerated salts of said compound.
 6. A compound of the formula (I) of claim 1, in which A is selected from the group consisting of the respective individual radicals

in which R_(A) ¹ is a radical selected independent of its respective occurrence from the group consisting of the respective individual radicals

B is a cyclic radical selected from the group consisting of the respective individual radicals

R¹ is chlorine; R2 is hydrogen; Y is a radical selected from the group consisting of the respective individual radicals

the tautomeric, enantiomeric and diastereomeric forms thereof, and the prodrugs thereof, and the physiologically tolerated salts of said compound.
 7. A compound of the formula (I) of claim 1, in which A is a radical selected from the group consisting of the respective individual radicals

R_(A) ¹ is a radical selected independent of its respective occurrence from the group consisting of the respective individual radicals

B is a cyclic radical selected from the group consisting of the respective individual radicals

R¹ is chlorine, R² is hydrogen, Y is a radical selected from the group consisting of the respective individual radicals

the tautomeric, enantiomeric and diastereomeric forms thereof, and the prodrugs thereof, and the physiologically tolerated salts of said compound.
 8. A compound of the formula (I) of claim 1, in which A is a cyclic radical selected from the group consisting of the respective individual radicals

in which R_(A) ¹ is selected from the group consisting of the respective individual radicals

B is a cyclic radical selected from the group consisting of the respective individual radicals

R¹ is chlorine, R² is hydrogen, Y is a radical selected from the group consisting of the respective individual radicals

the tautomeric, enantiomeric and diastereomeric forms thereof, and the prodrugs thereof, and the physiologically tolerated salts of said compound.
 9. A compound of the formula (I) of claim 1, characterized in that the radical is linked at position 5 of the oxindole ring structure.
 10. A compound of the formula (I) of claim 1, where the compound of the formula (I) is an enriched optically active isomer having an optical purity greater than 50% based on the optically inactive mixture of the isomeric mixture which rotates the plane of polarized light to the left (“negative rotation”).
 11. A compound of the formula (I) of claim 1, where the optically active isomer is an enantiomerically enriched diastereomer.
 12. A compound of the formula (I) of claim 1, where the property of “negative rotation” relates to the free base.
 13. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1b receptor subtype of less than about 100 nM.
 14. A compound of the formula (I) of claim 1, which has a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1a receptor subtype, where the quotient of Ki(V1a)/Ki(V1b) is greater than
 1. 15. A compound of the formula (I) of claim 1, which has a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V2 receptor subtype, where the quotient of Ki(V2)/Ki(V1b) is greater than
 1. 16. A compound of the formula (I) of claim 1, which has a selectivity for the vasopressin V1b receptor subtype vis-à-vis the oxytocin (OT) receptor, where the quotient of Ki(OT)/Ki(V1b) is greater than
 1. 17. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1a receptor subtype, where the quotient of Ki(V1a)/Ki(V1b) is greater than
 1. 18. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and a selectivity for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V2 receptor subtype, where the quotient of Ki(V2)/Ki(V1b) is greater than
 1. 19. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and a selectivity for the vasopressin V1b receptor subtype vis-à-vis the oxytocin (OT) receptor, where the quotient of Ki(OT)/Ki(V1b) is greater than
 1. 20. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and selectivities for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1 a receptor subtype and the vasopressin V2 receptor subtype, where the quotients of Ki(V1a)/Ki(V1b) and Ki(V2)/Ki(V1b) are in each case greater than
 1. 21. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and simultaneous selectivities for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V1 a receptor subtype and the oxytocin (OT) receptor, where the quotients of Ki(V1a)/Ki(V1b) and Ki(OT)/Ki(V1b) are in each case greater than
 1. 22. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1b receptor subtype of less than 100 nM and simultaneous selectivities for the vasopressin V1b receptor subtype vis-à-vis the vasopressin V2 receptor subtype and the oxytocin (OT) receptor, where the quotients of Ki(V2)/Ki(V1b) and Ki(OT)/Ki(V1b) are in each case at least greater than
 1. 23. A compound of the formula (I) of claim 1, which has a binding affinity Ki for the vasopressin V1 b receptor subtype of less than 100 nM and simultaneous selectivities for the vasopressin V1 b receptor subtype vis-à-vis the vasopressin V1a receptor subtype, the vasopressin V2 receptor subtype and the oxytocin (OT) receptor, where the quotients of Ki(V1a)/Ki(V1b), Ki(V2)/Ki(V1b) and Ki(OT)/Ki(V1b) are in each case greater than
 1. 24-39. (canceled)
 40. A method for the treatment and/or prophylaxis of at least one disorder to a patient in need thereof, wherein the disorder is selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplastie), ischemias of the heart, disorders of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurring during chemotherapy, travel sickness, affective disorders, anxiety disorders and/or stress-dependent anxiety disorders, memory impairments and/or Alzheimer's disease, psychoses and/or psychotic disorders, Cushing's syndrome, sleep disorders, depressive disorders, prophylaxis of vasomotor disorders, prophylaxis of disorders associated with drug withdrawal, and schizophrenia in a patient, where an effective amount of at least one compound of the formula (I) of claim 1 is administered to the patient. 41-50. (canceled)
 51. The method of claim 40, where the patient is a mammal, preferably a human or a non-human or a non-human transgenic mammal.
 52. A method for preparing compounds of the formula (I) claim 1, where the compounds of the formula (I) can be prepared by carrying out and/or carrying out analogously method steps known per se to the relevant skilled worker. 